Genedata developed the end-to-end oligonucleotide QC data workflow andprovided the consulting expertise throughout the entire project including thevalidation stage to help us achieve our goals on time and within budget.
Dr Juliet Padden, Laboratory Head Analytical Development at Bayer Pharmaceuticals, Wuppertal, Germany

AUTHORSDr Juliet Padden &Dr Heiner Apeler
Bayer Pharmaceuticals,
Wuppertal, Germany
INDUSTRY

Biopharmaceuticals
CUSTOMER SINCE

2006
ABOUT BAYER
PHARMACEUTICALSBayer Pharmaceuticals
focuses on researching,developing, manufacturingand supplying specialtyfocused innovative
medicines that provide
significant clinical benefitand value.
GENEDATA SOLUTION

Automating QC of Therapeutic
Oligonucleotides in a Regulated
Manufacturing Environment
Background
Bayer Pharmaceuticals obtained an exclusive license from Ionis Pharmaceuticals to develop
new oligonucleotide-based treatments for a wide range of medical conditions.
To support release testing and the imminent clinical trials of an advanced drug candidate, theBayer Analytical Development Team for Biologics was tasked with implementing a validated
drug substance and drug product release ID test that required establishing new analyticalmethods, standard operating procedures, and organizational responsibilities.
The tight go-live timeline and anticipated costs of any delay led Bayer to work together withour long-term partner Genedata to develop a confirmatory identification (ID) workflow ofoligonucleotide species by mass spectrometry so that an approved quality control (QC)
could be implemented and validated by Bayer’s Quality Assurance (QA) team.

CASE STUDY • GENEDATA EXPRESSIONIST • PRODUCT QUALITY MONITORING

Main Challenges
Implementing an oligonucleotide analytics workflowTo ensure safety and efficacy of the new oligonucleotide
drug substances, an ID test based on LC-UV-MS wastranslated from Ionis’ standard operating procedure(SOP) into Bayer’s quality management system (QMS)
and implemented in a new analytical environment. Thisrequired sourcing an analytical software that allows suchhighly customized implementation, while also supportingthe chosen instrumentation and ensuring interoperabilityof existing data formats. The SOP required measurement
and integration of data from multiple independent analytical
data streams — in this case UV and MS — to assessoligonucleotide ID (Figure 1). Automation of the workflow
was critical to both reducing the overall time required toperform the analysis and providing high confidence for theID assignment by removing any user input bias.
Satisfying GMP requirements
In order to support scheduled clinical trials, we needed
to develop the ID test for the batch release of a new
oligonucleotide drug product in a timely manner.
To enable the clinical deployment of the samples it was
imperative that the developed analytical solution could bedeveloped in a GMP environment. As a result, software
controls were needed to ensure data security, integrity, andtraceability and ultimately to confirm that every dose wassafe and efficacious.

Meeting a wide range of new analytical demands
Introducing new modalities and molecular species into
therapeutic development programs often requires a rangeof new and incremental capabilities, both technical andorganizational. In this case, our aim was to establish a new
QC protocol and ensure that quality assurance requirements
were met.
Moreover, developing novel therapeutics poses different
analytical challenges at different stages of the process.
While in QC ease-of-use and robustness are key, upstream
characterization and process development functions require
flexibility to support in-depth molecular characterization andevolving analytical capabilities.

Solution
Swift translation of the SOP into a streamlined dataprocessing, analysis, and reporting workflow
Genedata Expressionist enables timely implementation ofhighly customized MS solutions and thus the Ionis SOP
could be swiftly translated into an automated end-to-end
data processing, analysis, and reporting workflow.
Together with Genedata consultants, we further optimized
the workflow at every processing step to meet our analyticalneeds and ensured compliance in Bayer’s regulated
downstream operations, while adhering to the SOP.

Genedata Expressionist streamlines and automates complex analytical measurements, producing custom reports in any format required.

CASE STUDY • GENEDATA EXPRESSIONIST • PRODUCT QUALITY MONITORING

Support for data from multiple sources
The ID test was based on analytical measurements that used
MS and UV data independently and in combination. As anopen and vendor-agnostic platform, Genedata Expressionist
integrates seamlessly into the entire analytical process andenables us to directly import and process raw data fromdifferent instruments and combine these data streams in asingle analytical measurement.
Automating oligonucleotide data analysis
The Genedata Expressionist workflow developed for thisproject automatically determined the first acceptancecriterion (the oligonucleotide ID) by reporting the m/z valueof the main peak. A second acceptance criterion was sample
purity, which was derived from the UV data acquired in theanalytical run. Although the main oligonucleotide component
was visible in the UV data, impurities present in the samples
were typically not observable. Extracted ion chromatograms(EICs) of the earliest and latest eluting impurity components
in the MS data were used to determine the relevant areas of
the UV trace to be integrated for purity measurements.
The reported sample purity result was determined
automatically by the workflow. Numerous individual data
calculations ensured that the areas of UV interest werecorrectly determined and that blank signals had been
subtracted. The data integrity of the entire process —previously a highly laborious manual calculation process— was ensured by fully automating the data processing,analysis, and reporting workflow and operating it completely
within the Genedata Expressionist platform.

Implementation of a System Suitability Test to provide
confidence in results
Because the ID test result was subject to quality assurance
requirements, a range of system suitability tests (SSTs) —such as retention time stability, relative standard deviationof peak area, reference standard purity stability, and massaccuracy — also had to be performed to ensure confidence
in the ID test result.
All the SST results were determined automatically, and tosimplify review, a ‘traffic light’ report was created to provide
quick and easy identification of anomalous results (Figure 2).
Supporting deployment in a regulated GMP environment
To support deployment in regulated environments, Genedata
Expressionist workflows can be ‘locked down’ to ensure
data is processed in a manner that is not only reproducible
and standardized, but also in complete accordancewith the SOP. Out-of-the-box data security, integrity, andtraceability allowed Bayer to implement and validate the ID
test in the QC environment and meet its analytical and QA
requirements while managing tight timelines. Specifically,user authentication and role management prevented
unauthorized usage, electronic report submission and digital
signatures ensured smooth and immutable reporting, anda full audit log provided a total overview of the chain ofcustody for all results.

Compliance features of Genedata Expressionist that support deployment in regulated environments.

CASE STUDY • GENEDATA EXPRESSIONIST • PRODUCT QUALITY MONITORING

Benefits
An accelerated analytical process that met all our needs
The inherent flexibility of Genedata Expressionist alliedwith the expertise of the Genedata scientific and technicalconsulting team delivered an analytical process that met all
our requirements and was implemented and rolled out ontime and within budget.
The ability of Genedata Expressionist to integrate multiple
data streams facilitated a one-to-one translation of theexisting SOP into a fully automated workflow that after
training and validation could be performed by routine
users. Full automation of the workflow not only ensured
compliance with the SOP, but by eliminating manual process
bottlenecks, also dramatically reduced data processing timeby several hours.
Increased confidence and facilitated GMP deploymentAutomating the workflow eliminated the risk of errors due
to manual interventions and calculations, enhancing therobustness of the process and the reproducibility of results
and enabling us to make decisions with the highest levelof confidence. This confidence was further reinforced by‘locking down‘ the workflow, thereby ensuring data integrity.
The transparency and stepwise nature of the Genedata
Expressionist workflow enabled iterative optimization anddetailed assessment of the data at every stage of processing
and thereby facilitated verification of results. This, and theability to configure and document each processing step,
provided a clear demonstration of how data integrity wasmaintained throughout the entire process and greatly
facilitated the approval of the workflow solution into Bayer’s
regulated environment.

Consequently, Bayer’s regulatory experts could quickly
assess the workflow and perform Computer Systems
Validation (CSV), enabling the workflow to be established in
QC within project deadlines.
Proven support for streamlining processes
across the organization
Developing new classes of biopharmaceuticals — suchas oligonucleotides — brings new analytical challenges.
In this case, the trusted partnership between Genedata
and Bayer experts enabled an effective and fast solution
implementation across the entire analytical process —encompassing instrument selection and tuning; originator
SOP implementation; and data processing, analysis, andreporting — in a compliant environment. The flexibility,openness, and enterprise nature of Genedata Expressionist
enables Bayer to leverage the Genedata Expressionist
platform on multiple levels across the entire oligonucleotide
therapeutic development process, including upstream
process development.

Outlook
Bayer’s partnership with Genedata is built on a trackrecord of successful projects and Genedata Expressionist
has become the platform of choice for all our MS-based
biotherapeutics analytics. As we expand into the fieldof oligonucleotide therapeutics — and further into GxPenvironments — we are confident of being able to leverage
the software platform to develop and implement exactly the
analytical solutions we need. A key part of realizing thesesolutions we will be working closely together with Genedata
professional services, who offer us a range of support fromworkflow configuration to software development.

 ligonucleotide therapeutics bring new challenges, and we needed a trusted partnerO
who could assist us in addressing them. We appreciated that Genedata offered more thanjust software and that the customized solution — particularly the automation — was exactly
what we required.
Dr Heiner Apeler, Department Head Analytical Development Biologics at Bayer Pharmaceuticals, Wuppertal, Germany

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