The regulatory approval of several oligonucleotides over the past five years – combined with the recent headlines around rapid COVID-19 vaccine development – has created significant interest in the oligonucleotide (DNA/RNA) segment of the scientific industry. This includes everything from antisense oligonucleotides (ASOs) to lengthy gene transcript mRNA, as well as shRNA (small hairpin RNA), siRNA (small interfering RNA), CRISPR/Cas9 and anti-miR (anti-micro RNA).
The ability to rapidly create, study and formulate these nucleic-acid-based sequences and obtain authorization to provide timely therapeutic benefits to patients is more critical than ever. Robust data analytics from each unit operation – as well as throughout the processing flow continuum – can allow for fewer batch comparisons, thereby decreasing the molecular development timeline, in addition to decreasing the molecule’s cost to market.
To achieve these advances, however, there may need to be changes to currently accepted equipment design and utilization mechanisms for nucleic acid production. Many times, a preferred platform may be utilized for X operation, and yet another might be used for Y operation. This preference can be driven by hardware, software, industry expertise, customer support, lead time/availability and/or design; but, regardless, can create unnecessary imbalances in data output. The ideal arrangement would be to have a unified platform that could communicate with all equipment variations, allowing customers to choose any vendor without sacrificing core or regulatory type expectations for analytics capture and reporting. Such a solution would entail a future-proof, open platform communication (OPC) setup that would allow scalability and the ability to cover many instrument types.
Labor Reduction, Accuracy, Remote Operation
In the therapeutic oligonucleotide synthesis unit operation, many current manufacturing practices rely on manual, personnel-dependent measurement of the packed column bed height which is then entered into the synthesis recipe by hand. In an OPC environment, a bed height sensor on the column would automatically detect measurements and, due to its platform independency, then interface to convert this generic OPC request into a device-specific request for the synthesizer. This could allow the synthesizer to automatically adjust the processing recipe and/or the appropriate chemical deliveries for charges that are correlated to column volume and/or bed height. The result would be that the product impurity profile – and thus product safety and efficacy – has been maintained alongside the removal of potential human error.
An additional OPC benefit would be the integration and combination of controls that are used to create the chemical reagents necessary for successful therapeutic formation. Accurate composition and delivery, as well as the use of analytics to confirm compositional expectations of these reagents, will ensure product consistency and process accuracy. New technological advances are quickly being made in nucleic acid chemistry, whether it be in production and optimization, new chemistries, delivery and uptake for the patient, or clinical efficacy. These rapid developments may not be easily incorporated into standalone equipment platform due to potential secondary and tertiary consequences, thus requiring lengthy testing and qualification assessment.
An OPC setup also allows for the ability to monitor and easily operate hardware remotely, or via a mobile device, enabling resource efficiency. This could be financially beneficial for smaller sites that cannot afford to invest in additional personnel shifts, yet possess the demands to run operational activities during off-shift hours. The use of an OPC-based platform would remove the need for more traditional techniques, such as remote desktop access. The incorporation of OPC could also allow for simultaneous user access, which may not be feasible in a remote desktop environment.
Driving Quality and Productivity
Distinct and detailed analytics throughout the oligonucleotide process can provide greater assurance of product quality, product safety, process accuracy and quick identification of areas requiring process improvement. The monitoring of multiple data streams during each coupling cycle can help identify variable output data, even when all appropriate processing parameters have been set/controlled. For example, product quality that can be understood early in the process, combined with process understanding founded in analyzed data, can help with planning downstream operations in a manner that ensures the final product is of proper safety, identity, strength, purity and quality (SISPQ– 21 CFR 210.1(a)).
For example, if a 21-mer (base length) oligonucleotide has 98.5% efficiency for each coupling, the resulting theoretical purity ceiling will be ~72.8%; but if that efficiency is improved to 99% for every base coupling, the theoretical purity ceiling will now become ~81.0%. Although this 0.5% change may not appear significant from an empirical value perspective, proper analytics can help assure that this migration in efficiency can make a significant positive alteration to the attained purity. Not insignificantly, this purity improvement could result in fewer executed unit operations or a lower cost of goods. In such a case, a conjugated oligonucleotide may not require the use of a chromatography/purification operation if the purity is high enough, therefore earlier recognition of the product purity might drive certain processing decisions.
OPC-driven analytics may also provide the possibility of using data to determine execution of maintenance for more efficient downtime management. Most often, time-based execution of maintenance (every 3 months, 6 months, etc.) frequencies have been outlined or prescribed in the production environment to help ensure that production equipment is running as smooth as possible for as long as possible. The use of analytics connected and based upon a central platform could provide the data to demonstrate a more accurate justification/timing to perform any necessary maintenance (‘predictive” maintenance).
The use of analytics for process accuracy can be beneficial to confirm product safety (against a clinically accepted impurity profile) and can also assist with product/process investigations should there be a need to compare against historical batches. Sensors that can monitor delivery flow rate and delivery volume with a high data frequency attainment rate can provide not only significant data, but also assurance that the process was executed as expected.
OPC Avoids ‘Standalone’ Pitfalls
A standalone system that is not OPC compliant/compatible could inhibit industrywide advancement as the incorporation of new sensors or new technology would require assurance that the existing hardware or software is not impacted by the upgrade. Further, standalone systems likely contain proprietary methods for accessing “behind the scenes” analytics used to help diagnose, or preventively identify, an equipment-related issue. OPC-ready systems should allow quicker analysis and diagnosis of any imminent issues.
The synthetic creation of oligonucleotides requires the integration of many systems, including those that demonstrate quality. Many of the quality systems are integrated into the regulatory commitments to ensure that product efficacy and safety are maintained. While there is heavy focus on product efficacy, and rightfully so, process efficacy would most certainly benefit from an OPC-type design.