There is a new report which has gone on to review the processing of the present state of sterile oligonucleotide drug product. This includes recommendations to help in the evaluation and development of the terminal sterilisation processes, as well as an additional exploration of the present regulatory expectations for the oligonucleotide drugs.
DeCollibus et al. pinpointed that the two of the most common methods when it comes to sterilising the parenteral drug products happen to be membrane sterilisation and terminal sterilisation.
In the case of terminal sterilisation, the drug product gets sterilised in the final container once the filling and finish is concluded. The method goes on to provide a better sterility assurance than the membrane sterilisation as well as aseptic processing. That said, DeCollibus et al. noted that not all the drug products happen to be amenable to terminal sterilization, which usually involves exposure to pretty high heat as well as ionising radiation.
With regards to the terminal sterilisation process of the oligonucleotides, recommendations have been provided by authors to formulate the development, assess the change in purity as well as impurity profile post the terminal sterilisation and also selecting the right container closure.
In case of membrane sterilisation, the stream of the product gets sterilised by membrane filtration and thereby filled into pre-sterilised containers in a processing environment that is aseptic. That said, for more stable molecules, there is a possibility that only moderate changes in the impurity profile may occur, thereby making the decision of which sterilisation method to use more difficult. This apparently opens the door when it comes to opinion differences between regulators as well as manufacturers.
It is well to be noted that all the marketed oligonucleotide products happen to be delivered for parenteral delivery as sterile preparations. The authors of the study highlighted the fact that there happens to be a clear regulatory expectation that TS is indeed a preferred method in case of sterilising parenteral products. The paper also referred to the 2019 EMA guideline on sterilisation of the medicinal product, excipient and primary container, which put forth the fact that proper and meaningful efforts must be made when it comes to enabling TS such as including formulations exploration, closure of containers and also process parameters which may go on to elevate the implementation of TS processes successfully. Although the guidance goes on to provide a greater insight when it comes to the perspective of the regulators and also covers the concepts that were not addressed previously, DeCollibus et al. mentioned that there is still some degree of uncertainty in reference to how to put this guidance in practice. Besides this, there is still ambiguity surrounding the subjective language that is used in the guidance, like substantial efforts or what can be considered an acceptable risk.
The paper went on to mention that the major concern for drug developers is balancing the risk involved in negatively impacting product quality during TS against the perceived risk of aseptic processing, like the release of a nonsterile unit.
The authors have also gone on to list a few of the many technical considerations which add to the complexity, such as reliance on the platform as well as similarities in antisense oligonucleotide formulations, impurities, manufacturing processes, as well as toxicology profiles. All these add weight to every decision as they have the ability to set the precedence in a manufacturers pipeline development and that too across the industry. As per DeCollibus et al., a unified understanding of the subject matter is the prime requirement, thereby highlighting that the European Pharma Oligonucleotide Consortium can enable the communication of such considerations on behalf of the manufacturers of oligonucleotides.