Microbial control
When synthesising oligonucleotides, its vital to have a holistic microbial control strategy in place. Downstream of chemical synthesis, the drug substance is a non-sterile product. Synthetic oligonucleotide production uses an excess amount of water and neutral pH conditions which could potentially promote microbial growth.
Therefore, the drug substance needs to be further formulated into a sterile drug product intended for either subcutaneous, intravenous, or intrathecal administration. Furthermore, the end product will need to meet raising health authority expectations to ensure patient safety.
Health authority expectations
Current advice from health authority agencies spans a few published guidance documents. United States Pharmacopeia (USP) chapter 1115 mentions bioburden control of nonsterile drug substances. The FDA also has a draft guidance document which conceptualises microbiological quality for nonsterile drug manufacturing.
In Europe, the EMA has shared guidance specifically for oligonucleotides which Tremell said was very helpful, but didn’t necessarily contain a lot of information about microbial control. Furthermore, the EU’s GMP Annex I concerns mostly sterile medicinal drug products but does contain some recommendations for non-sterile drug substances. And there are two European Pharma Oligonucleotide Consortium (EPOC) white papers that share technical and regulatory considerations with a section on microbial control.
Risk-based approach
Trumell’s team engage in a holistic microbial control strategy. This involves monitoring all aspects of the manufacturing process from start to finish. Facility, utilities, environment, personnel, equipment, and materials are all considered to ensure a reliable and safe product quality.
To oversee all these aspects, the team takes a quality risk assessment approach as per ICH Q9 guidelines using tools like Hazard Analysis Critical Control Points (HACCP). Overall, Trumell stressed that there needs to be an understanding that all monitoring aspects are interrelated. These risk assessments are regularly documented and reviewed.
ASO case study
Trumell then presented a case study of a single stranded ASO. Here, they implemented multiple microbial control measures such as bioburden reduction, filtration, and tight endotoxin specifications. The clinical team required the product to be essentially endotoxin-free, and the implemented controls successfully met these stringent specifications. Tremmel emphasised the importance of continuous optimisation and collaboration across various disciplines to ensure reliable and safe product quality.