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Quality aspects to be considered in oligonucleotide manufacturing



*Corresponding author

1. BioSpring GmbH Alt Fechenheim 34 Frankfurt, Germany

2. BioSpring GmbH 400 W. Cummings Park, Ste. 1725 #111 Woburn, MA 01801-6579, USA


Oligonucleotides have long been a tool of molecular biology and used in medical agent applications as early as 1978. Synthetic oligonucleotides can be produced via commercially available automated synthesizers following the same basic process consisting of synthesis, removal of the protecting groups, purification, desalting, and lyophilisation. Given that there are a multitude of modifications that can be incorporated into these synthetic oligonucleotides, the real challenge is to develop suitable protocols and methods that ensure necessary quality and yield of the end product. In this article, we take a closer look at the quality aspects to be considered during the manufacturing of these synthetic oligonucleotides. Specifically, we discuss the concept that the quality of product is a reflection of the entire production process and therefore the quality of starting materials must also be considered in the discussion. Key to the analysis of oligonucleotide quality is the availability of suitable detection methods for impurities, whether they originate from the process or the raw materials used in the process. Overall, analytically accessible specifications and recorded process documents should be in place in order to ensure the reproducibility of the production process and equivalence of the material being produced over time.


Since the conquest of the polymerase chain reaction (PCR), oligonucleotides have been among the oldest tools of molecular biology. Oligonucleotides and their derivatives also have a long tradition in use as medical agents. As early as 1978, Zamecnik and Stephenson (1) succeeded at inhibiting the in vitro virus production of the Rous sarcoma virus with the help of synthetic DNA oligonucleotides. The uniqueness of oligonucleotides in pharmaceutical use lies in the way they work at their target. The high specificity and the simplicity with which the candidate drugs can be selected and subsequently be produced in large quantities make oligonucleotides attractive development candidates for many pharmaceutical companies. This is also important from another perspective. The US drug approval agency, the Food and Drug Administration (FDA), has to date categorised oligonucleotides as being more similar to ‘small molecules’ as opposed to recombinant proteins, which are considered “biological”. This means that the conditions are much more attractive for the development and production of such agents.
Oligonucleotides are synthetically pro ...

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