A relatively new class of parenteral drug products on the market - therapeutic oligonucleotides – poses new challenges to the pharmaceutical manufacturing process. For example, an important prerequisite is the product-specific implementation and validation of an unequivocal analytical identity (ID) test for incoming goods and for release testing of injectables. Therefore, QC laboratories must implement new technologies and techniques to meet these needs, preferentially based on profound in-house scientific experience to enable fast and successful method transfer from third parties.
At Vetter, such knowledge and experience are gathered and distributed by the Development Service with new analytical techniques mainly assigned to the Analytical Science Laboratory (ASL). Integrative, multidisciplinary approaches are typically included and executed in cooperation with academic and pharmaceutical partners.
Within method life cycle, revision and verification of established methods is approached. With respect to oligonucleotides, we raised questions such as whether implemented classical pharmacopeial methods (e. g. the determination of pH, osmolality and density) can be applied on these products without restrictions¹ and adapted our methods accordingly.
A more sophisticated, recent project investigated the applicability of a method for analytical ID testing of oligonucleotides in detail and is based on the determination of melting temperatures (Tm) by UV spectrophotometry. The procedure was challenged in various ways in order to define its limits of application². To achieve this, model oligonucleotide sequences and variants thereof were designed, synthesized and analyzed. Even single base mismatches or single nucleotide deletions and insertions in the sequences led to significant changes in the measured Tm of the corresponding oligonucleotide duplexes. A high specificity of the method was confirmed as subtle changes in oligonucleotide sequences were detectable with high precision. These results indicate that this simple and fast to perform, yet highly specific analytical method could be used as ID testing for oligonucleotides in a pharmaceutical QC environment. The outcome of these studies is currently presented and discussed with expert audiences³ ⁴ ⁵ and has been submitted for publication⁶.
New opportunities continue to open up. For example, establishing and validating an analytical platform method⁷ based on the current knowledge that would ease method transfer, thereby complying with quality standards and fulfilling customer needs. Clientele without a complete method portfolio for transfer would certainly benefit from our knowledge and experience.
Dr. Alexandra Heussner is an accomplished interdisciplinary scientist and laboratory manager within the Development Service of Vetter in Ravensburg, Germany. During her earlier work on numerous academic research projects she contributed to the understanding of the toxicology of natural toxins and pharmaceutical drugs and supported method development and implementation by integrating biological sciences, information technology and statistics. She received her PhD in Applied Sciences from the University of Sunderland, UK, and after many years in academic research, she joined Vetter in 2016. She is currently involved in analytical procedure implementation, development and validation with her team in the Analytical Science Laboratory. She is a member of the Parenteral Drug Association (PDA).
Dr. Melanie Zerulla-Wernitz is the Head of the Analytical Science Laboratory and therefore responsible for a diverse team of excellent scientists combining various natural and applied sciences. She holds a PhD in natural science from the University of Konstanz, Germany. After many years in preclinical development Dr. Zerulla-Wernitz joined Vetter in 2004. Her career started in the quality control department but lead her after a little while into the upcoming Development Service. With a one-year excursion to Vetter Development Service in Chicago, she is continuously leading the Analytical Science Laboratory and constantly working on the enlargement of its service and analytical portfolio.
Headquartered in Ravensburg, Germany, Vetter is a family-owned, global leading contract development and manufacturing organization (CDMO) with production facilities in Germany, Austria and the United States. Currently employing more than 5,500 individuals worldwide, the company has long-term experience in supporting biotechnology and pharmaceutical customers both large and small. Vetter services range from early stage development support including clinical manufacturing, to commercial supply and numerous packaging solutions for vials, syringes and cartridges. As a leading solution provider, Vetter appreciates its responsibility to support the needs of its customers by developing devices that contribute to increased patient safety, convenience, and enhanced compliance. Great importance is also given to social responsibility including environmental protection and sustainability. Learn more about Vetter at www.vetter-pharma.com.
¹ Kappenstein, K., Identification of critical parameters for the analytics of nucleic acid-based parenteralia in a pharmaceutical environment, Vetter Pharma and University of Hohenheim, 2019.
² Schuler, S., Establishing a method for identity testing of therapeutic oligonucleotides by determination of melting temperatures, Vetter and University of Konstanz, 2021.
³ Heussner, A.H., Emerging therapeutic oligonucleotides – analytical challenges accepted, PDA UPS conference, 05-06 Oct 2021.
⁴ Schuler, S. et al., Emerging therapeutic oligonucleotides – ID testing, PDA UPS conference, 05-06 Oct 2021.
⁵ Schuler, S. et al., Challenging oligonucleotide ID testing, 8th Annual Oligo Networking Event, 23-25 Mar 2021.
⁶ Heussner, A.H. et al, Investigating Tm method specificity using oligonucleotide sequence variants. Submitted to PDA J Pharm Sci Technol for publication, 2021.
⁷ Krause, S., Using analytical platform technologies to support accelerated product development – concept review and case study. Submitted to PDA J Pharm Sci Technol for publication, 2021.