Biotechs Still Underestimate CMC – And Pay The Price

By Louis Garguilo, Chief Editor, Outsourced Pharma

Consultants tell me those who should know better – from executives to project managers – overestimate their ability to manage CMC activities.

That’s surprising, and suggests a fundamental refresher is in order as we approach yearend.

CMC, a vital section on a regulatory submission, is the documented account of what a drug is, how it’s manufactured, and how the sponsor establishes that the product is sufficiently understood, and controlled for its intended stage of development.

This data/information is required in submissions ranging from an IND supporting clinical investigation to later applications seeking marketing approval. The detail evolves with the product and its stage of development. One look at the FDA's CMC information requirements for INDs should dispel any notion that CMC is a simple documentation exercise.

Think of CMC as a map of a drug and its manufacturing process. It gives regulators a basis for assessing identity, quality, purity, and strength.

Overestimate your proclivity to get this section right and you risk undermining human and financial resources, and potentially the commercial approval of your drug.

In cell and gene therapy, for example, reported clinical-hold concerns have included inadequate potency assays, stability concerns, manufacturing changes requiring comparability evidence, and uncertainty about whether the clinical material adequately represents material used in nonclinical studies.

The Utilization Of CDMOs

Solving for these challenges does not, though, require large sums of money or or completing every conceivable CMC activity before a first clinical trial.

Good CMC planning is phase appropriate. It identifies what must be established now, what can legitimately evolve as development progresses, and what risks accompany a decision to defer work. Consulting directly with regulators along the way is counseled.

In fact, FDA's current guidance on first-in-human Phase 1 INDs illustrates the distinctions. For certain CDER-regulated small-molecule and recombinant-biologic products, FDA has clarified that some information such as analytical method validation data and certain stability information need not necessarily be complete at the initial submission.

The Agency estimates that applying what we might call logical flexibility could reduce application-development time by up to 12 months.

But this, too, implies biotechs should have experienced CMC professionals understanding how some early decisions can affect the program as it advances. Every dollar must be considered against competing demands, but postponing a necessary activity can create greater costs later through rework, delayed clinical supply, or regulatory questions that could have been anticipated.

This is where an experienced CDMO makes a difference.

Today’s most capable external partners bring development, analytical, manufacturing, and technology-transfer experience to a relatively inexperienced sponsor.

CDMO can help identify early must haves, anticipate process challenges, generate essential data, and build the documentation needed to support the development program.

Of course, with today’s novel approaches and programs, experience must be relevant to the product, modality, and development stage.

Selecting a CDMO primarily based on capacity, price, or availability may undermine your long-term goals.

A strong argument can be made for including a CMC professional among a biotech's early hires, or from the outset engaging an experienced consultant (perhaps until the need for a dedicated position becomes paramount).

So whether it’s via an experienced internal resource or consultant, or trust in your CDMO, ensure a professional with appropriate expertise is advising the sponsor organizations on development priorities, coordinating scale ups and manufacturing, and recognizing challenges before they occur.

Some might caution on relying too extensively on your CDMO. Outsourcing CMC work doesn’t take away the sponsor's responsibility for its development program.

A CDMO can generate your process data, analytical results, manufacturing records, and technical documentation. But it is your regulatory submission.

Prepare and guard it well.

As touched on above, a focused pre-IND meeting can help sponsors and CDMOs discuss their plans and the CMC information needed to support initial clinical studies.

Bring the relevant CMC and regulatory professionals you are working with into those discussions. Prepare questions, share the necessary background information, and listen closely to the agency.

Fundamentals In Action

Let's return to the fundamentals.

A good start is with the International Council for Harmonisation guidelines, including the ICH quality guidelines, which provides detailed frameworks for pharmaceutical development, quality risk management, and quality systems.

But here’s a quick review of the fundamentals:

• Chemistry – The characterization of the drug substance and drug product, including identity, composition, purity, impurities, stability, and the analytical methods used to understand and assess them.
• Manufacturing – The description of how the drug substance and drug product are made, including relevant raw materials, production processes, equipment, facilities, and changes made as the process develops and scales.
• Controls – The measures used to establish that materials and products meet appropriate quality standards. These include specifications, in-process checks, analytical testing, release criteria, and stability monitoring.

Responsibility to meet requirements are often shared across by regulatory and quality professionals, R&D and analytical teams, and supply chain and manufacturing professionals

But it is the CMC professional bringing those contributions together. Select those professionals wisely.

Communicator And Coordinator

CMC professionals are often responsible for messaging up into the C-suite, board, and other stockholders. All parties should understand the cost of particular activities, and how each connects to overall development, supply, regulatory milestones, and program risks.

Often, this includes explaining the consequences of defering work now to save funding.

Communication with external partners is equally important as across internal functions; every component of the supply chain should understand its respective responsibilities and how their work fits together.

A clinical manufacturing batch, for example, cannot be considered independently of the earlier data and results collected; analytical methods used; applicable release requirements; stability needs; and the timing of clinical trials. CMC leadership ensures these activities are planned, connected, and documented.

The CMC professional has close affiliations with regulatory affairs, quality assurance, analytical teams, and again, the CDMO to ensure all data and quality information is complete, consistent, and fit for the intended purpose.

Consultation is needed for development of suitable analytical methods, specifications and release testing, stability programs, and the documentation needed to investigate and resolve unexpected results or deviations.

Paramount is ensuring the respective contributions are integrated and reflected accurately in the regulatory submission.

We’ll end there, the part most everyone does place importance – the actual writing of the CMC related sections of regulatory submissions.

However, without all the work, guidance and coordination described above, the best of CMC section authors will not be in a position to succeed.