Edition 5 / September 2019
Associate Director, Sales & Key Account Management,
CordenPharma currently provides a number of key services critical for the oligonucleotide field by developing and manufacturing synthetic lipids for oligonucleotide drug formulations, various carbohydrates for oligonucleotide-targeted drug delivery, and / or oligonucleotide drug product manufacturing, packaging & logistics for clinical trials.
Oligonucleotide drugs were initially met with high expectations for the rapid development of treatments for unmet need indications with a genetic component not achievable by small molecule approaches. Two main categories of oligonucleotide therapeutics, antisense oligonucleotides (usually 15-25mer DNA sequences that bind to messenger RNA) and short interfering RNA (siRNA) therapeutics (double-stranded switch for RNAi that silences gene expression) are just now on the verge of fulfilling their promise.
In the early days of oligonucleotide therapeutic development, the limitations and complexities of delivering oligonucleotides to their site of action, the cell nucleus of a particular tissue, was not elucidated. Very simplistically, oligonucleotides needed to survive nuclease degradation in the bloodstream, reach the target tissue, achieve cellular uptake into the cell and then traffic to inside the cell nucleus, all while demonstrating efficacy and avoiding off-target toxicity.
Perhaps not surprisingly, with nearly four decades of hindsight since the advent of oligonucleotides as potential drugs, there have been just seven oligonucleotide-based USFDA drug approvals, with four of those coming since 2016. This acceleration of approvals was driven by the learnings from previous attempts and hundreds of publications that have produced the body of understanding around oligonucleotide drug delivery and the resultant rationally-designed strategies to address these delivery challenges.
Delivery strategies range from chemical modification of the oligonucleotide backbone to evade nuclease degradation, nanoparticle formulations, conjugation to targeting moieties or pharmacokinetic enhancers like PEG, and co-administration of other drugs to affect trafficking to combinations thereof. With these strategic delivery technologies and some clinical successes, investor enthusiasm is back, as reflected in the more than 400 oligonucleotide-based development programs from pre-clinical through phase III.
All of these different strategies – deployed individually or in combination – have CMC implications. Oligonucleotides are considered synthetic APIs (in theory no potential for chromatin incorporation) and are regulated by the FDA’s Center for Drug Evaluation and Research (CDER), with the exception of vector-based or promoter-driven oligonucleotide therapeutics, which are regulated by the Center for Biologics Evaluation and Research (CBER). While synthetically manufactured, oligonucleotide therapeutics are nonetheless high molecular weight complex biomolecules with unique challenges compared to other therapeutic classes, even when compared to other oligonucleotide therapeutics.
Some of the diverse classes of oligonucleotide therapeutics under development are of the RNAi type, which are double-stranded and include small-interfering RNA (siRNA), single strand antisense splice modulators and aptamers, as well as conjugates (e.g., small molecule, carbohydrate, peptides, proteins, lipid, PEG conjugates & even aptamers). This diversity and the limited regulatory track record means there are no specific ICH or FDA guidelines that address the quality concerns for oligonucleotide therapies. A CDMO with experience in this evolving space will be an important asset to consider when choosing a program partner.
cGMP clinical and commercial manufacturability of Drug Substance and Drug Product may be more straight forward for delivery strategies that are solely chemical in nature (backbone modifications, conjugates or co-administration with other APIs). Those formulation and drug product strategies that include lipid nanoparticles, liposomes or other polymeric nanoparticle formulations introduce greater manufacturing & QC analytical testing challenges and parameters to control & test with respect to particle size, drug loading and particle stability that are well beyond the general synthetic drug testing requirements. This complexity of oligonucleotide therapeutics and formulations has driven large & small pharma and biotechs to outsource manufacturing to CDMOs with specialized capabilities.
Robust and advanced analytical testing capabilities are required at the API & Drug Product CMOs, and should be a key consideration in your selection. Oligonucleotide testing will share general similarities to small molecule testing with regard to requirements of appearance, identity, assay and impurities. However, oligonucleotides present unique challenges introduced by the relatively large size, multitude of chiral centers, double-stranded nature of siRNA drugs and even three-dimensional conformation in the case of aptamers. An aptamer will have a tertiary structure required for potency and specificity that must be maintained throughout drug product manufacture. A bioassay for potency after drug product manufacture may be the only practical way to confirm correct tertiary structure was maintained. In the case of siRNA, duplex oligonucleotide Drug Product testing may also require assay and purity testing for the double and single-strand oligonucleotide drug species.
All of the different sterile parenteral oligonucleotide based drugs require aseptic fill & finish installations for drug product manufacture. The oligonucleotide sequences – whether modified or encapsulated in a carrier system – will not survive thermal terminal sterilization and the nanoparticle itself may degrade.
Further, long-term stability in solution – especially that of RNA oligonucleotides – is limited, due to sensitivity to hydrolysis. Therefore drug product manufacturing will frequently include a lyophilization (freeze-drying) step to remove the fill solvent. The key benefits of a lyophilized dosage form are longer shelf-life at room temperature and maintenance of potency with overall simplification of the dose administration process.
Just considering the more straight-forward case of chemically-modified oligonucleotide drugs, lyophilization process development capability is a key consideration for the selection of an oligonucleotide drug product manufacturer, which should ideally also have oligonucleotide experience and a Quality by Design (QbD) driven approach to drug product development, combined with the necessary lyophilization development capabilities and equipment installations.
An in-house lab-scale lyophilization unit, where experiments on conditions can be systematically investigated and eventually transferred to cGMP production, will ensure optimal CDMO efficiency. Ready access to a high sensitivity differential scanning calorimetry (DSC) capability will also be indispensable for the quantitative evaluation of excipients, surfactants, buffer salts and critical parameters like the glass transition temperature (Tg), which determines the amorphous state of the drug formulation and is a critical measurement to drive formulation development, process development & storage of the drug product.
QbD applied to lyophilization development will help ensure robust optimization of the process, linking data generated in the development lab around combinations of formulation possibilities and lyophilization conditions. A matrix of oligonucleotide pre-formulation physical and chemical properties as well as the formulation excipients and process solvents must be systematically evaluated under a Design of Experiments (DoE) protocol to ensure solvent removal while avoiding API degradation. Experimental parameters include solvent system pH, lyophilization temperature, cycle-time and moisture content – and even the vial composition must be considered. For instance some oligonucleotides may degrade in amber vials due to the iron oxide content.
For oligonucleotide drugs that can be successfully formulated as a stable solution, thereby averting lyophilization, cartridges and single chamber pre-filled syringes are options beyond standard liquid vial fill. Our CordenPharma Caponago aseptic manufacturing facility has more than 120 million units of capacity per year across Pre-Filled Syringes, cartridges & vials. Filling volumes range from approx. 1 mL to 20 mL and use the latest ready-to-fill nest & tub technology. CIP/steam-in-place capabilities minimize risk of endotoxin and other microbial contaminants.
In summary, the continued trend towards oligonucleotide drug delivery strategies and future commercial approvals will require increasing CDMO expertise. CordenPharma offers continued support for the emergence of oligonucleotide drugs as a mainstay of therapies for highly unmet need diseases. Our services provide cGMP supply of key biomolecules such as synthetic lipids for oligonucleotide drug formulations and carbohydrates for oligonucleotide-targeted drug delivery, as well as oligonucleotide drug product development, manufacturing, packaging & logistics from clinical trials through commercialization.
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