A selection of insights presented by Susanne Kindermann, Technical Regulatory Manager at Roche
David Orchard-Webb looks back on a popular presentation, given by Susanne Kindermann, Technical Regulatory Manager, Roche at TIDES Europe in 2020, which explored key existing regulatory guidance concerning CMC for oligos.
Susanne Kindermann gave an introduction to the contemporary regulatory guidance on oligonucleotides as therapeutics, the different types of oligonucleotide used by the pharmaceutical industry and a quick description of how they are manufactured.
Then she dove into the CMC challenges and opportunities; including the work of the European Pharma Oligonucleotide Consortium (EPOC).
To date, there is a total of 11 oligonucleotide therapeutic products approved worldwide. Compared to small molecules and biologics (35 and 10 respective FDA approvals last year alone), oligonucleotides are niche.
This niche has not been met with specific regulatory guidance, so companies are mostly using elements of existing guidance. As a result, there is a lot of uncertainty. There are similarities and differences between oligos, small molecules and biologics.
Therapeutic oligos include antisense, siRNA, miRNA, aptamer, decoy, and recently CRISPR.
Full synthetic chemistry makes oligos analogous to small molecules; however, they also share some properties of the larger biologics. Like most biologics, they are not orally available and are usually a sterile injectable.
The impurity profile of an oligonucleotide such as Inclisiran is more complex than small molecules because of the oligo size and the manufacturing process. Due to the EPOC classification system, (see below and further reading) good reasons why such impurities are acceptable are documented.
CMC challenges that regulators are most concerned about include control of product related impurities, starting materials and their control, identity testing of the oligo API, and microbiological control strategy.
A position paper is in the reference section regarding impurities. Kindermann believed global harmonisation is required to deal with these CMC regulatory challenges and that a common synthesis platform for the many types of oligos is an advantage.
Kindermann asked, “how can we communicate and share more work between industry and also at the end of course with the regulators?” She then introduced the European Pharma Oligonucleotide Consortium (EPOC). This consortium was formed in 2018 by seven founding members.
The mission statement of EPOC is: “Through innovative collaboration, identify areas for harmonisation of oligonucleotide CMC development and regulatory strategies, and propose good practices and solutions to influence the external regulatory environment; ultimately expediting patient access to life-changing medicines.”
Concluding her presentation Kindermann noted that the approved therapeutic oligo market is growing, but there is still a lack of global regulatory guidance.
This can lead to inconsistent expectations from the different global regulatory areas, which can, in the worst case, slow down the drug development process. There is a need to obtain some global alignment.
To accomplish this, additional guidance from the regulators would be helpful, in addition to continuing the dialogue across the industry with the regulators, to come up with proposals for oligonucleotide control and other topics.
TIDES Europe, workshops and joint publications like those by EPOC are invaluable for aligning mindsets to the regulatory challenge.