It’s akin to hiking up Mount Kilimanjaro, report Steven Lal, Lead Scientist in CMC Analytics, and Yoonsik Kim, Senior Scientist in Analytical Method Development at Samsung Biologics.
In both settings –– drug development and extreme climbs –– it helps to have a guide. Although biopharma companies can acquire the necessary tools and maps to summit independently, contracting an integrated team of expert guides can make the journey far more efficient and predictable than going alone … especially when challenges arise.
One of the most important areas for guidance in biologics drug development is the design of chemistry, manufacturing and controls (CMCs). Industry wide, there is growing awareness of the need for a customised CMC approach when developing therapeutics.
When done well, CMCs serve as a strong foundation for future filings, approvals and reliable commercial manufacturing. They’re also critical in terms of offsetting risks.
Among other pitfalls, insufficiencies in CMC strategy and execution have been identified as a key driver of refuse-to-file decisions from the US FDA, subsequently causing major delays in development timelines.1
For many biopharma companies, the challenge of developing strong CMCs comes with finite resources. Many don’t have the capital, time or expertise needed to design and execute a robust CMC strategy in-house.
As detailed below, an innovative and experienced CDMO partner can fulfil this need by delivering flexible product-specific services. A good guide should demonstrate these skills along with a commitment to every therapeutic programme. No two journeys to the summit will look the same and a good CMC strategy should reflect that.
Innovative CMC strategies for innovative therapies
Chemistry, manufacturing and controls are critical to keep patients safe throughout the lifecycle of a drug. In practice, they involve a series of activities in which the critical specifications to develop and produce a new therapeutic product are defined.
For biologics, CMCs include functions such as molecular characterisation and purity testing (chemistry), cell line development, upstream and downstream processing (manufacturing), quality control, stability testing and regulatory documentation (controls).
Together, these activities create a safe, consistent and effective GMP manufacturing strategy for consistently high-quality products.
Although patient safety is the universal goal, CMC strategies need to be heavily customised based on the modality, process, indication and countless other factors.
Compared with small molecule drugs, biologics tend to be highly complex and heterogeneous, making them difficult to structurally and functionally characterise.2
Ongoing testing and tight tolerances for key metrics are needed at every stage — from raw material testing to batch release — to ensure a consistent product.
Biologics are also susceptible to different impurities, such as bioburden, mycoplasma or viruses, either introduced through the supply chain or during the manufacturing process.3
The need for innovation and customisation doesn’t stop there. A new wave of analytical processes and technologies is being developed to accommodate new fusion proteins, bispecific antibodies and antibody-drug conjugates (ADCs).
Development processes for these newer more complex modalities are unlikely to fit existing platforms and may be particularly prone to acquiring in-process and product-related impurities.
For example, higher resolution and more sensitive mass spectrometers have allowed newer techniques –– such as protein sequence variant analysis, host cell protein identification by liquid chromatography-mass spectrometry and multi-attribute monitoring –– to streamline and assess product quality throughout product development, even for low level species.4
All told, CDMOs may need to become more agile and leverage their project track record to assess product quality during process development.
For bispecific antibodies (BsAbs) built on the knob-in-hole system that’s commonly applied to enhance chain assembly, ongoing testing is needed to identify aggregates, fragments or mispaired antibodies.
Given BsAbs require more complex expression systems than a traditional antibody owing to their dual-targeting nature, developing a stable cell line capable of consistently producing a sufficient yield can be a significant challenge.5
When it comes to developing ADCs, biopharma companies need to ensure the quality of the large-molecule antibody, its highly cytotoxic small-molecule payload and the linker technology. Optimising these three distinct components requires more in-depth characterisation and adherence to strict specifications.6
Developers also must establish a highly reproducible process for effective conjugation … and regulatory groups need to evaluate the delivery of the payload and its stability throughout transport.
As with any therapy, the investigational new drug (IND) or biologics license application (BLA) filings for these products require rigorous documentation that cover all aspects of the manufacturing processes, product-specific control strategies and analytical methods used.
This is a tall order for any small or mid-sized biopharma company to tackle alone. Many generalist CDMOs may also struggle if they are not fully integrated and dedicated to the innovative and highly customised development and manufacturing demands of monoclonal antibodies or newer biologic modalities.
Tapping into specialised experience
CMC strategies must adapt and evolve to new modalities without compromising quality, efficiency or adherence to regulatory standards. This requires innovative technologies and processes, which many CDMOs can offer.
However, there is a second crucial component that sets the most qualified CDMOs apart: experience. Experience is what ties all these strengths and capabilities together, establishing the best path to market, setting realistic development timelines and keeping the programme on track.
A CDMO that has ushered dozens of biologic therapies through IND and BLA filings knows how to incorporate innovative technologies and insights into existing regulatory frameworks.
They understand how to ensure that the correct assays are done for the appropriate materials that fit desired properties and at the right stage in development … all while avoiding any unnecessary or inefficient steps. From every angle, experienced CDMOs think long-term and build scalability into their CMC strategies.
Fundamentally, knowledgeable CDMO teams can offer advice about the overall developability and manufacturability of an early and late-stage asset.7
Does the molecule have the potential to advance through IND and BLA filings or are there significant risks involved? Can it feasibly be manufactured at scale in a stable format for distribution?
These insights, acquired through direct experience with hundreds of biologics programmes, can help clients to proceed with the right therapeutic candidate the first time around.
Once initiated, experienced CDMOs have a wealth of CMC tools and expertise to navigate challenges or unexpected situations. They can help to troubleshoot technical bottlenecks, such as low titres, yields or quality, which can occur when producing complex molecules.
Solutions to these bottlenecks may not always be intuitive, but having a CDMO partner with experience in CMC development can make the process as smooth and efficient as possible.
Like our guide on a mountain, seasoned CDMO partners know the landscape and have a well-developed toolkit of solutions to increase output while maintaining quality.
When evaluating CDMOs, biopharma companies should ask about quality management systems, standard operating procedures (SOPs) and what mechanisms the teams have in place to triage unexpected results.
With real-time monitoring, in-process control and other intelligent systems to track critical parameters such as temperature and pH, it’s possible to catch unexpected excursions early before major consequences arise.
Comparing this with past events using historical data can allow the team to course-correct without compromising timelines.
Partnering for success
Chemistry, manufacturing and controls for biologics help to chart a safe, efficient and reliable path from drug discovery to commercial manufacturing. They help to ensure that every therapeutic dose is safe for human use.
An innovative and experienced CDMO is an invaluable partner for this journey, establishing the best possible foundation for the product while preventing costly missteps. It’s the most direct path to the summit of the mountain, facilitated by an innovative and experienced guide.
References
- https://pink.citeline.com/PS143806/FDA-RefuseToFile-Decisions-Are-Rare-But-CMC-And-Ignoring-Agency-Advice-Are-Often-Triggers.
- www.raps.org/News-and-Articles/News-Articles/2024/2/biologics-CMC-regulatory-technical-advice.
- https://doi.org/10.1007/s00216-021-03648-2.
- https://doi.org/10.3390/molecules28083392.
- www.worldpharmatoday.com/articles/the-role-of-cdo-in-complex-biologics-development/.
- https://doi.org/10.1016/j.xphs.2023.09.007.
- www.biopharmaboardroom.com/opinion/82/1360/successful-development-and-manufacturing-of-complex-biologics-with-integrated-cmc-solutions.html.
