Table 2.

Summary of Key Considerations in Assessing Solution and Powder Active Pharmaceutical Ingredient

Consideration	Solution API	Powder API
Stability	Oligonucleotides generally have enough stability for long-term storage in solution (>3 years either as a liquid or as frozen). Other stresses may be at higher risk in solution (ie, freeze/thaw, light, high temperature for some manufacturing processes).	Lyophilized oligonucleotides exhibit stability for >3 years in general under refrigerated and frozen conditions.
API manufacturing	Choice of concentration techniques dependent on final concentration needed for API. UF/DF may achieve up to 40–150 mg/mL concentration though the maximum may be sequence dependent. TFE or other evaporative process needed if high concentration is required.	UF/DF and lyophilization well established to isolate the API and transfer to the DP manufacturing process. Lyophilization step is time consuming (up to 5 days per batch).
Microbiologic considerations	Greater focus on microbial control, as aqueous environment may present a higher risk. Freezing is an option to prevent microbial growth. Controls have been historically well established for use in biologic manufacturing.	Powder API, particularly stored at −20°C, is less likely to promote microbial growth. Microbial growth is low risk.
Solution API packaging	Leachables are of greater concern with an aqueous environment, though acceptable leachable profiles have already been demonstrated with common containers. Supply chain implications of shipping larger masses of liquid, potentially under frozen conditions should be considered.	Powder API in drums stored at −20°C should have no leachable concerns and are easy to transport and store.
Integration with DP manufacturing	Greater efficiency by removing steps that are time consuming and potentially have critical/key parameters associated, that is, dissolution and compounding steps for fully formulated ready-to-fill API. Additional unit operations can be added (dilution, additional compounding) with other solution API presentations that still potentially provide manufacturing efficiency.	Requires dissolution, compounding, and dilution steps, thus adding more complexity to the DP manufacturing process.

API, active pharmaceutical ingredient; DP, drug product; TFE, thin film evaporation; UF/DF, ultrafiltration/diafiltration.