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Project

Een duik in het Oligoproject

A team of Advipro colleagues is working on Janssen Pharmaceutica's Oligo project. The A-Team likes to tell how they started this and what their responsibilities were during the project. But Oligo, what exactly is it?

What is Oligo?

The expression of genetic material runs from DNA through RNA to proteins. Over the past century, efforts to develop new drugs have mainly focused on protein-targeting using different types of compounds, including small molecules and monoclonal antibodies. Here, the drug affects the action of one or more specific proteins. However, not all types of proteins can be treated using this strategy.

An alternative to this classical method is to modulate DNA or RNA. This can be achieved using oligonucleotides. Oligonucleotides are single- or double-stranded small synthetic nucleic acid polymers (≈20-more) with a known sequence. If this sequence is complementary to a particular segment of DNA or RNA, also called an antisense oligonucleotide, it can then form a duplex with it and thus inhibit gene expression. In this way, it affects protein function.

Zo’n oligonucleotideproces bestaat uit volgende stappen:

  1. Synthesis: Dit is de chemische synthese van relatief korte fragmenten van nucleïnezuren met een gedefinieerde chemische structuur (sequentie). Om het gewenste oligonucleotide te verkrijgen, worden de bouwstenen (amidites) sequentieel gekoppeld aan de groeiende oligonucleotideketen in de volgorde die vereist is voor de sequentie van het product. Deze synthese vindt plaats in een kolom gevuld met een drager.
  2. Cleavage & Deprotection: Na voltooiing van de sequentie wordt het product van de vaste fase (=drager) gesplitst, naar een oplossing gebracht, van bescherming ontdaan en verzameld.
  3. Purification: Deze ruwe oligonucleotide-oplossing wordt vervolgens gescheiden van onzuiverheden via chromatografie.
  4. Ultrafiltration / Diafiltration (UFDF): Hierbij wordt het oligonucleotiden ontdaan van zouten en worden ze verder opgeconcentreerd.
  5. Annealing: Bij deze optionele stap kan er gekozen worden om van een enkele streng oligonucleotide naar een dubbele streng te gaan aan de hand van annealing.
  6. Lyofilisatie: Tot slot wordt de overtollige hoeveelheid water via vriesdrogen verwijderd en bekomt men het finale product

Such an oligonucleotide process consists of the following steps:

  1. Synthesis: This is the chemical synthesis of relatively short fragments of nucleic acids with a defined chemical structure (sequence). To obtain the desired oligonucleotide, the building blocks (amidites) are sequentially linked to the growing oligonucleotide chain in the order required for sequencing the product. This synthesis takes place in a column filled with a carrier.
  2. Cleavage & Deprotection: Upon completion of the sequence, the product is split from the solid phase (=carrier), transferred to a solution, deprotected and collected.
  3. Purification: This crude oligonucleotide solution is then separated from impurities by chromatography.
  4. Ultrafiltration / Diafiltration (UFDF): Here the oligonucleotides are stripped of salts and further concentrated.
  5. Annealing: In this optional step, one can choose to go from a single strand oligonucleotide to a double strand by annealing.
  6. Lyophilization: Finally, the excess water is removed via lyophilization and the final product is obtained

Upgrade Oligonucleotides Center of Excellence

In order to be able to self-produce oligonucleotides suitable for toxicological batches or First In Human (FIH) clinical production, Janssen Pharmaceutica decided to upgrade their Oligonucleotides Center of Excellence and equip it with cGMP equipment. The purpose of this Center is to expand internal capabilities and competencies to ensure timely and reliable delivery of clinical products and to develop new processes.

Fit For Purpose

Since the focus of this process is only on FIH purposes, it was decided to go for a "slimmed-down" qualification approach, the Fit For Purpose (F4P) approach. The focus here is mainly on maximum delivery of FAT / SAT / commissioning tests, no strict separation of the different qualification phases, fewer reviews and approvals from QA,... This leads to a faster completion of the qualification and significantly less paperwork and documents.

Validatie diagram
Diagram

Advipro contribution

In order to complete this large project with ambitious timelines, Advipro was called in. The A-team took care of the compliance part of the project for equipment, utilities & facilities as well as execution systems (CSV).

Lien - Equipment

My role within the project initially focused on the equipment part of the project. A lot of mobile vessels, reactors, skids,... had to be purchased, tested and qualified.

I was responsible for:

  1. Delivering all qualification documents (URS/IA, protocols, reports, etc.) These were prepared using the Fit For Purpose approach explained earlier. The biggest challenge here was defining what did/did not have to be done within the Fit For Purpose framework as this was new to everyone within the project team.
  2. Establishing the overarching Change Control and the various equipment specific Change Controls. This includes coordinating and reviewing/processing all CC actions (over 1000 actions).

As "last woman standing" it is currently my task to complete the complete compliance part for the Oligo project, i.e. equipment as well as utilities & facilities and execution systems.

Lien Kerremans

Rani - Utilities & Facilities:

Within the project, I started supporting Lien in writing the qualification documents based on the Fit For Purpose Equipment Testing. I went to several FATs in the Netherlands of the mobile vessels, which are used in the different steps of the oligonucleotide production. My tasks here were: to review the documentation and to perform some functional tests.

After a short period of supporting the equipment part of the project, it was necessary to fully focus on the Utilities & Facilities part of the project.

I was responsible for:

  1. Drawing up all qualification documents (URS, IA, qualification and safety protocols, qualification and safety reports, etc.) and this according to the two different methods of the two different responsible departments within Janssen Pharmaceutica.
  2. Drawing up the Utilities & Facilities specific Change Controls.
  3. The follow-up and coordination of the delivery of evidence of these CC actions.

I was able to hone my skills with regard to coordination within this project because I had to communicate with different contractors, the different departments within J&J, ... .

Rani Vanhoudt

Kristof - Execution Systems

As a compliance engineer, I was mainly involved in the automation part of the project. Here I was introduced to everything around execution systems, PLCs, data integrity, and so on. For Oligo, specific use was made of PCS7, the process control system responsible for, among other things, monitoring, visualization and (in limited cases) direct control of equipment. PCS7 was involved in the change controls of many systems, which made it very complex.

PCS7 required full validation. I was involved from design review through functional testing. I was mainly involved in documentation, such as preparing a URS, RA and IOQP, among others. I also had the opportunity to perform some functional tests related to data integrity.

Kristof Van den Neucker

Sara - Project Manager

During the Oligo project, I stepped into the project as the first person from Advipro. I was involved in writing the project qualification plan and defining the approach that would be followed for compliance within the project. After the start-up of the team, I gradually transferred my tasks to the team. In the project I was responsible for the overall planning of the compliance tasks and budget of the entire Advipro A-team.

From Advipro's side, we were always flexible to provide the resources the project needed. Furthermore, I monitored the workload of the team and jumped in when needed.

Sara Knaeps

And how did Janssen Pharmaceutica experience working with a class A-Team?

"There was a real team spirit between Advipro and rapid integration into the project team. It was an exciting process where the team was able to use resources flexibly and ensure timely delivery and aftercare of quality documentation. The project management was right on target with this motivated team!"

- Jurgen Verbraeken, Senior Principal Engineer