Product Specifications: Why We Analyze
The point of oligonucleotide analysis is to assure that products meet specifications. According to Daniel Capaldi, Ph.D., vp for analytic and process development at Isis Pharmaceuticals, “a specification is a critical quality standard, proposed by the manufacturer and approved by regulatory agencies. It is a contract among the manufacturer, the regulatory agencies, and the patient, which describes the quality criteria that the drug substance or drug product will meet consistently.”
Interestingly, therapeutic oligonucleotides, as well as some peptides and radiopharmaceuticals, are excluded from the scope of International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline Q6A. Evidently the ICH expert working group lacked direct experience with oligos, and time-restrictions prevented their consideration within the guidance.
“We believe that the spirit of Q6A, and that of the related impurities guidelines Q3A and Q3B, which also categorically exclude oligonucleotides, do, in fact, apply to oligonucleotide therapeutics, but that certain details of the guidelines require modification,” Dr. Capaldi explains.
As with small molecule drugs, oligonucleotide specifications are not designed to establish full characterization, but rather focus on critical quality attributes to ensure safety and efficacy. This is achieved by confirming identity and strength and through impurity characterization.
As one would expect from their structure, oligonucleotides present unique challenges. Impurity testing is relatively straightforward with small molecule drugs, but with oligos impurities can only be practically controlled as groups of related structures. “The size and complexity of oligonucleotide drugs often requires the application of sophisticated analytical techniques,” Dr. Capaldi adds.
“The relatively limited data obtainable by analyzing an oligonucleotide drug also enhances the importance of other aspects of the control strategy. For example, at Isis we have invested heavily in process and product knowledge, in-process controls, and process validation, and we view these and other quality-by-design principles, such as risk assessment and adherence to current good manufacturing practices, as equally important components of any strategy designed to assure quality.”