How Adept CMC Management Blazes A Trail To The Clinic

By Life Science Connect Editorial Staff

As therapeutic development continues to accelerate in response to market demand, fast-track programs, and innovative economic models, CMC (Chemistry, Manufacturing and Controls) management is often misunderstood to the detriment of drug development programs. Properly executing CMC management — and CMC outsourcing, in particular — not only mitigates risk, but it also provides opportunities to accelerate pharmaceutical developers’ rush to clinic for even the most complex therapies.

How CMC Can Hasten a Program

Newer modalities do not benefit from the near-plug-and-play dynamic of small-molecule chemistry, formulations, or monoclonal antibody (mAb) manufacturing, but an innovative CMC strategy can be a powerful facilitator for speed to clinic. Responsibility for creating that strategy rests firmly in the hands of the sponsor company. CDMOs and consultants can help, but overreliance on them to instill quality or to make difficult data- and risk-based decisions is both imprudent and slow.

Particularly among startup companies, it is vital to secure a process development and manufacturing expert as soon as possible, whether hired in-house or outsourced. In part, this is because such an expert can immediately begin assessing the CDMO landscape to help create a strategy for drug development, manufacture, and delivery. This expert also should offer expertise in navigating a global clinical supply chain.

Their guidance helps to ensure prospective CDMOs and other partners offer specialized expertise, infrastructure, and technologies specific to your drug type. As in several other areas of development, strategic use of consultants is increasingly necessary to support CMC, since it usually is not fiscally prudent for most companies to hire all the required expertise. Moreover, nascent biotechs typically are structured very lean. However, to achieve high-end CMC results, the cost of hiring an in-house head of clinical and a head of CMC is warranted to ensure ample time and attention are dedicated to completing tasks optimally.

Do Not Let CMC Be Undermined

Lack of comprehensive knowledge about each CMC task, its purpose and the resources it requires, usually is the key obstacle to accelerating the process. Another common issue is a disconnect between the C-suite and technical individuals responsible for the project. For example, executives may prematurely fundraise on the back of an announcement that the company will begin its first clinical trial before the end of the year.

A sponsor’s initial focus can unduly center on a candidate drug’s biology, with insufficient thought dedicated to how the drug will be made. This blunder is due, to some extent, to industry complacency stemming from advances in antibody manufacturing and the commoditization of manufacturing. A feeling of false equivalence can leave some companies unprepared to develop and manufacture new modalities.

Gap and Risk Analysis Fill the Blanks

A strong foundation for CMC management is built upon investing foresight and humility: accept what you do not understand before you need to know it. Common sense dictates gap and risk assessment covering knowledge and equipment should begin as early as possible. Ensure company management has a clear understanding of each problem’s depth and impact so they can collaborate with technical personnel top-to-bottom on a strategy to fill those gaps — whether through consultants, partnerships, or hiring — as well as craft more accurate public messaging. If time and budget allow, gap and risk analysis also can be conducted by a third-party expert to help ensure objective findings.

Understand Current and Upcoming Regulator Expectations

To take advantage of regulators’ specialty programs such as Fast Track, companies must realistically assess the public health value of their proposition to the Agency. With some rare exceptions — for example, the difficult-to-achieve Breakthrough Therapy designation — the FDA is unlikely to grant a project additional flexibility, even to support a new modality, unless the product has the potential to substantially improve standard of care or it addresses an untreated patient population.

Additionally, in terms of providing regulatory clarity, a platform guidance detailing rules around oligonucleotides would be valuable toward accelerating the associated CMC processes. Such a document could help clarify cases involving minor changes in sequence and rely on preexisting data — such as that generated for process validation or analytical method development/validation — to support a developer’s claim that one change is not going to dramatically change the process outcome.

Indeed, under the Platform Technology Designation Program,¹ there is room to start using more science- and risk-based arguments to leverage preexisting data — particularly for mRNAs, synthetic oligonucleotides, and some synthetic peptides. More products are available every day to reference as successful evidence of the process’ ability to deliver quality material consistently. Still, the term “platform” must arrive at an agreed-upon definition to ease drafting a guidance. The industry understands that word differently from regulators, and the definitional misalignment is complicated even more by the existence of a third, legal definition within statutes.

Don’t Just Rush to Clinic; Set the Pace

Three key tenets are valuable in operationalizing the rush to clinic:

1. Accept that clinical milestones will almost always be driven primarily by company funding, partnering opportunities, etc.
2. Accept that human and financial resources for CMC will be constrained.
3. Do not let points 1 and 2 be excuses for failure.

The most effective way to accelerate CMC regardless of role is to make anyone’s problem everyone's problem. Modern drug development allows no room for siloed communication due to fixed lead times, physical constraints, and unforgiving timelines. Relentless transparency, as a company principle, may or may not make you faster, but it will eliminate the last-minute surprises that occur when some CMC elements are allowed to become afterthoughts.

Examine the product profile and weigh what is required for that product to be successful versus the cost you are willing to pay to manufacture and supply it. At project outset, high-level understanding of the product profile and the manufacturing process is sufficient. If one understands their modality well, they understand the biology. Then, they can work with the translational medicine and discovery research teams, as well as clinicians, to understand the drug’s potential risks.

Making decisions within the context of a specific therapeutic area and molecular biology — and securing partners who specialize in that area — helps companies generate a more accurate gap and risk assessment. In turn, this leads to better-informed decision-making when creating CMC management strategy. To learn more, watch Outsourced Pharma Live’s “How Can CMC Keep Up With The Rush To The Clinic?” on demand. The virtual event, hosted by Outsourced Pharma Chief Editor Louis Garguilo, assembles the expertise of consultants, CMDOs, and sponsor companies in an hour-long exploration of CMC strategy.