Growth of targeted therapies gives rise to need for flexible manufacturing of smaller API quantities
Targeted therapies, those developed to either block or increase the function of a specific target in order to treat a given disease, are on the rise. That’s been true for the past decade. They are prevalent in the field of oncology and immunology, but these potentially improved treatments are also being explored for diabetes and other diseases. The hope is that ”precision medicine” (also sometimes referred to as personalized medicine, although they’re not quite the same), will be able to identify which patients can benefit from targeted therapies, which are based on genetic, environmental, and lifestyle factors.
Indeed, recent guidance from the U.S. Department of Health and Human Services (HHS) and FDA includes the observation that in a population of patients with the same clinical disease, the heterogeneity in the molecular etiology may result in different responses to a particular targeted therapy. What works for one group of patients may not work for another with the same clinical diagnosis. Consequently, the FDA last year approved a record number of precision drugs, a trend that is likely to continue.
How does this impact drug development and manufacturing? This article will focus on the changing CRO/CMO/CDMO landscape as targeted therapies continue their upward trajectory.
Right-sizing API development and manufacturing for targeted therapies
The shift to precision medicine heralds a move toward relatively smaller clinical trials that segment patients based on certain characteristics. It also means fewer patients for each individual therapy. For the pharma industry, this represents a sea change from the historic focus on developing and manufacturing broad-based therapies for large numbers of patients for treatment of such ailments as heart disease. Statins, for example, are taken by 15 million people in the U.S. and many more worldwide. With precision medicine, the number of patients is greatly reduced, perhaps to numbers as low as those for orphan drugs, where patient numbers can be 200,000 or fewer
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How will sponsors adapt? They will need to work with contract development and manufacturing organizations (CDMOs) that are flexible and can more easily scale to varied pharma needs. CDMOs such as PCI Synthesis can easily accommodate them at the scale required, large or small. At the largest CDMOs, which are geared for developing and manufacturing large quantities of drugs, the smaller batch projects can wind up at the end of the queue. That’s as it should be – CDMOs who largely do business with drug giants such as Merck or J&J should continue to favor their most lucrative customers.
For smaller batches, pharma companies might consider looking beyond their traditional CDMO partners to find those that are highly flexible, accommodating, and that would welcome their business. We have written a great deal about choosing a CDMO that could be helpful in introducing sponsors to smaller drug developers and manufacturers as they right-size their API manufacturing resources to better align with today’s realities.
Choosing the right-sized CDMO
In choosing a CDMO to develop and manufacture targeted therapies it never hurts to check whether the prospective CDMO has won industry awards and has stellar references.
To assess API development capabilities be sure to conduct a site visit as well as a thorough audit that follows the basic approach of the FDA’s system-based inspection program.
The seven most important GMP manufacturing capabilities to evaluate include:
- Kilo lab preparation and scale up.
- Equipment and facilities.
- Preventive maintenance program.
- Master batch records.
- Cross-contamination prevention.
- Warehouse organization and raw material sampling.
- Staffing of manufacturing team.
CRO tasks: API development costs likely won’t change much
Even when small quantities of an API are required, what’s not likely to change appreciably is the time and cost involved in drug material development. Whether a program requires 50 grams or 500 kilos of a drug substance, the chemistry involved in developing the new chemical entity (NCE) remains a labor-intensive, rigorous and time-consuming process.
Choose a CDMO with a scale-up process, important in minimizing expensive surprises when moving into the costlier GMP manufacturing suite, and that has the range of equipment necessary for small or larger-scale manufacturing. The CDMO should be equipped to manufacture the range of quantities needed for Phase I to the increased material required for Phase III trials and commercialization.
As well, there is a definite advantage to finding and working with a CDMO with experience and expertise in a particular type of chemistry related to the current project, which many smaller CDMOs possess. Less trial and error results in moving projects along faster.
CMO: Smaller CDMOs are a good fit for manufacturing smaller quantities
When it comes to GMP manufacturing of targeted therapies, flexible CDMOs that can manufacture the smaller API quantities required for Phase I trials tend to be quicker and more adept at GMP manufacturing than larger companies. The biggest CDMOs are more focused on sizeable Phase II trials likely to move to large-quantity commercialization. They are not well suited to manufacture 500 gm of a sophisticated API. We on the other hand can prioritize early stage work and move projects ahead to meet the ever-shrinking timelines besetting the pharmaceutical industry.
Precision medicine and targeted therapies require development and manufacturing of drugs in smaller quantities for the smaller number of patients who can benefit from the therapy. Pharmaceutical companies can bring products to market faster and at somewhat reduced cost by shifting API development and manufacturing to smaller, more flexible CDMOs who will prioritize smaller projects and who may have deep expertise in similar chemistry.