A relatively new class of parenteral drug products on the market – therapeutic oligonucleotides – pose new challenges to the pharmaceutical manufacturing process. For example, an important prerequisite is the product-specific implementation and validation of an unambiguous analytical identity (ID) test for incoming goods and for release testing of injectables. Therefore, QC laboratories should implement new technologies and techniques to meet these needs, preferably based on in-house scientific experience to enable rapid and successful method transfer from third parties.
At Vetter, this knowledge and experience is gathered and disseminated by the development department with new analytical techniques primarily assigned to the Analytical Sciences Laboratory (ASL). Integrative and multidisciplinary approaches are usually included and executed in cooperation with academic and pharmaceutical partners.
In the method life cycle, the review and verification of established methods is addressed. Regarding oligonucleotides, we have raised questions such as whether the classical pharmacopoeia methods implemented (e.g. determination of pH, osmolality and density) can be applied to these products without restrictions¹ and adapted our methods accordingly.
A more sophisticated recent project investigated the applicability of an analytical oligonucleotide identification test method in detail and is based on the determination of melting temperatures (Tm) by UV spectrophotometry. The procedure has been challenged in various ways in order to define its limits of application². To achieve this, model oligonucleotide sequences and their variants have been designed, synthesized and analyzed. Even single base mismatches or single nucleotide deletions and insertions in the sequences resulted in significant changes in the T measured.m corresponding oligonucleotide duplexes. 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, but very specific analytical method could be used as an identification test for oligonucleotides in a pharmaceutical QC environment. The results of these studies are currently presented and discussed with an audience of experts³ ⁴ ⁵ and have been submitted for publication⁶.
New opportunities continue to open up. For example, establishing and validating an analytical platform method⁷ based on current knowledge that would facilitate method transfer, thereby meeting quality standards and meeting client needs. Customers without a full portfolio of transfer methods would certainly benefit from our knowledge and experience.
Dr Alexandra Heussner is an accomplished interdisciplinary scientist and laboratory manager in the Vetter Development Department in Ravensburg, Germany. During her previous work on numerous academic research projects, she contributed to the understanding of the toxicology of natural toxins and pharmaceutical drugs and supported the development and implementation of methods by integrating biological sciences, technologies information and statistics. She received her PhD in Applied Science from the University of Sunderland, UK, and after many years in academic research she joined Vetter in 2016. She is currently involved in implementation, development and validation of analytical procedures with his team in the analytical science laboratory. She is a member of the Parenteral Drug Association (PDA).
Dr Melanie Zerulla-Wernitz heads the Analytical Science Laboratory and is therefore responsible for a diverse team of excellent scientists combining various natural and applied sciences. She holds a doctorate in natural sciences from the University of Konstanz, Germany. After many years of preclinical development, Dr Zerulla-Wernitz joined Vetter in 2004. Her career started in the Quality Control department, but soon after took her to the future Development Department. With a one-year field trip to the Vetter Development Service in Chicago, she continuously runs the Analytical Science Laboratory and is constantly working to expand its portfolio of services and analyzes.
Based in Ravensburg, Germany, Vetter is a leading family-owned global contract development and manufacturing (CDMO) organization with production facilities in Germany, Austria and the United States. Currently employing more than 5,500 people worldwide, the company has a long history of supporting biotechnology and pharmaceutical customers, large and small. Vetter’s services range from early stage development support, including clinical manufacturing, to commercial sourcing and numerous packaging solutions for vials, syringes and cartridges. As a leading solutions provider, Vetter values its responsibility to meet the needs of its customers by developing devices that help improve patient safety, convenience and compliance. Great importance is also given to social responsibility, including environmental protection and sustainability. Learn more about Vetter at www.vetter-pharma.com.
?? Kappenstein, K., Identification of Critical Parameters for Analysis of Nucleic Acid-Based Parents in a Pharmaceutical Environment, Vetter Pharma and University of Hohenheim, 2019.
² Schuler, S., Establishment of a Method for Testing the Identity of Therapeutic Oligonucleotides by Determination of Melting Temperatures, Vetter and University of Constance, 2021.
³ Heussner, AH, Emerging Therapeutic Oligonucleotides – Accepted Analytical Challenges, PDA UPS Conference, 05-06 Oct 2021.
⁴ Schuler, S. et al., Emerging Therapeutic Oligonucleotides – Identification Tests, PDA UPS conference, October 05-06, 2021.
⁵ Schuler, S. et al., Defying Oligonucleotide Identification Testing, 8th Annual Oligo Networking Event, March 23-25, 2021.
⁶ Heussner, AH et al, Investigating Tm specificity of the method 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.