From a manufacturing standpoint, Agilent continues to see many early-stage programs and new customers, according to James Powell, GM, with a growing emphasis on more exotic, complex oligo conjugates to enhance delivery. “I think the industry has embraced the idea that there will not be any one delivery technology—no one-size-fits-all solution. Instead, delivery strategies are likely to be tissue-specific, which has resulted in a broad range of compounds we’re being asked to manufacture,” as well as demanding novel analytical solutions for characterizing conjugated oligos.
Girindus America (member of the Solvay Group), a CMO that specializes not only in oligo manufacturing but also produces small molecules, is leveraging this expertise to manufacture components for the increasingly complex oligo delivery systems in development and the conjugated oligo-based compounds being evaluated and scaled up for preclinical and clinical evaluation, according to Kathryn Ackley, Ph.D., director of project management.
She asserts that Girindus has a broad customer base and sees continued interest in RNA production, particularly for siRNA applications, in single-stranded antisense oligos, LNA-based oligo therapeutics, and oligos used as adjuvants in vaccine production.
The company recently hired additional chemists to enhance its oligo conjugation expertise and has invested in advanced analytical technology, such as UPLC. Girindus draws on the expertise of its sister company within the Solvay Group, Peptisyntha, for access to peptide sequences that are being conjugated to therapeutic oligos to improve their delivery and targeting.
At the upcoming “TIDES” meeting, Dr. Ackley will participate in a panel discussion of a white paper in development intended to provide a consensus view on the issues related to impurities in oligonucleotide-based active pharmaceutical ingredients. There is no formal regulatory guidance on this topic. This work represents an industry-wide effort in which multidisciplinary, informal working groups have formed to discuss best practices in the area of oligonucleotide production, including chemistry, manufacturing, and control and oligo drug safety, for example.
For Hüseyin Aygün, Ph.D., CSO at BioSpring, a GMP-certified producer of therapeutic oligos, the take-home message from the recent “AsiaTIDES” meeting is the focus on novel delivery methods, with talks on topics such as nanotechnology and the move toward formulated antisense compounds instead of naked oligos to improve uptake and reduce therapeutic doses.
Process and Product Validation
At BioSpring, the number of projects in the corporate pipeline continues to increase. In particular, the past year has brought a growing demand for aptamers both with and without pegylation, notes Dr. Aygün.
Expressing the need for “new analytical techniques to characterize final and intermediate aptamer products,” he describes the company’s addition of differential scanning calorimetry (DSC) to its analytical toolbox and the positive feedback from customers, who are requesting DSC measurements to help characterize oligo and apatamer formulations and assess their stability.
A key advantage of DSC compared to chromatography and other analytical techniques, according to Dr. Aygün, is its ability to characterize the structure and dynamics of oligos at high concentrations—concentrations that would be present during manufacturing. As an example, he describes the use of DSC to determine the propensity for single-stranded oligos present at high concentrations to aggregate in different formulation buffers.
In addition to rising demand from BioSpring’s existing customer base, the company is seeing an influx of new customers entering the oligo drug development arena and ordering GMP oligos to support toxicology studies and clinical-development projects. Dr. Aygün notes a growing number of inquiries in recent months from Japanese biotech and pharma companies.
Trends in downstream processing include moving quality control points earlier in the process, according to Dr. Srivatsa. She points to two key analytical techniques that “have made a meaningful difference” in overall quality assessment: UPLC, yielding a complete impurity profile in a shorter amount of time; and LC/MS, giving manufacturers a “tighter handle on their processes and helping with process optimization.” Mass spectrometry is “probably not too far off from being a routine manufacturing tool.”
At Agilent, the company’s commercial-scale manufacturing facility in Boulder, CO, is up and running and producing large-scale batches for late-stage clinical development programs, which, according to Powell, “are looking very promising. We’re looking to support multiple NDA’s over the next few years.”
Paul Metz, director of operations at Agilent, who oversees the commercial facility, describes some of the challenges and opportunities the industry is managing with the adoption of the most recent GMP regulations and subsequent guidances for regulatory compliance and filings—ICH Q8 covering pharmaceutical development data, ICH Q9 related to quality risk management, and ICH Q10 regarding quality systems.
These guidances further clarify what regulatory authorities expect in terms of the design of processes, with an emphasis on process understanding and building quality into the process rather than demonstrating quality by testing a finished product against specifications.
Agilent has developed an internal framework for a risk-based approach to oligo development and manufacturing that integrates QbD and process analytical technology (PAT) concepts into its scale-up and process validation programs.
“These support our clients’ commercialization strategies and worldwide regulatory filings,” says Metz. Based on this QbD approach, “we have developed rugged, small-scale models for every unit operation, giving us the ability to project at small scale what we will see at large scale,” and to use the models to optimize process parameters before scale-up, he adds.
The PAT approach incorporates increasingly rapid inline and online process analytical technologies to yield real-time information on the synthetic and downstream purification processes. Agilent utilizes the analytical power of mass spectrometry to identify and track raw material and process-related impurities throughout the process and gauge their impact on product quality attributes.
Access to these types of data throughout the production of oligos from early- to late-stage clinical development may provide clients more flexibility in their product registrations with options such as continuous verification (CV). Implementation of CV involves continuous monitoring, evaluation, and adjustment, as needed, of the process. It represents a move away from validation as a discrete exercise and toward a life cycle approach to process validation.