With New Chemical Entities the Only Constant is Change

According to the FDA, New Chemical Entities (NCEs) are drugs that contains no active moiety which has previously been approved by the FDA in any other application submitted under section 505 of the Federal Food, Drug, and Cosmetic Act.  A NCE is granted exclusivity by the FDA, which gives the license holder limited protection from new competition in the marketplace.

It’s important to note the difference between an NCE and a New Molecular Entity (NME). While an NCE has no active moiety, an NME contains an active moiety that has not yet been approved  by the FDA or marketed in the U.S.

NCEs begin life as chemical molecules and ultimately emerge as key ingredients in life-saving drugs. Yet, despite their urgency in treating disease, nearly one-third of drug candidates fail in preclinical studies – and often this can be attributed to compromised NCEs. Added to that, identifying an NCE and developing it as a new drug can take upwards of 15 years, at costs in the hundreds of millions of dollars.

Why are there so many challenges when manufacturing NCEs? The key reason is uncertainty.  As with anything new, the pathway to their creation is completely unchartered territory. No one can be quite sure of how the NCE molecule will react under different conditions, how long it may take to achieve the desired outcome or what problems could arise in raw materials.

For these reasons, most NCE development and manufacturing is outsourced to Contract Development and Manufacturing Organizations (CDMO)s who can leverage their expertise, experience and library of best practices.  Since successfully navigating FDA regulations can be challenging, it’s advisable to carefully scrutinize the CDMO’s track record of adherence to the highest cGMP standards. Contaminants, hazards and quality control in manufacturing are key issues that could result in the FDA’s delaying the trial. With time pressures always at the forefront, setbacks can be devastating and costly – yet many could have been avoided.

Below are four other key challenges in developing NCEs and how your CDMO can help to assuage them.

1. Quality issues in raw materials. Sourcing the highest quality raw materials whenever possible is a critical concern of CDMOs, yet even with the most diligent sourcing and strongest supplier alliances, there are many things that can go wrong. They can fail to meet the specifications set forth in the Drug Master File (DMF) or you could find foreign matter in the raw materials which could cause major damage to reactors and other equipment.So how can CDMOs ensure they are receiving the highest quality raw materials they can? The key is to properly vet your suppliers through on-site visits, references and audits; while also having a back-up supplier on hand. Additionally, once a CDMO has a good, trustworthy supplier, it’s important to maintain a strong relationship and establish ongoing communication.
2. Too little yield. Organic compounds are never pure. When isolated from natural sources or created through organic reactions, they always contain other compounds. Before carrying out the qualitative and quantitative analysis of organic compounds that is needed to characterize them, it is very important to purify them as much as possible.Purification is a critical step in drug manufacturing, helping to eliminate unwanted materials that can be hazardous or compromise drug efficacy.  While there will always be a certain amount of impurities in NCEs, the goal of a current Good Manufacturing Processes (cGMP) facility is to minimize these impurities.
3. Problems in scale-up. Manufacturing an NCE in a kilo lab and scaling up in the plant can produce very different results. When bringing a molecule to the cGMP suites for first time, the process can take much longer, given the need for greater supervision and quality control. It’s often difficult to exactly simulate the cGMP suite in the lab so sometimes new impurities show up or materials don’t crystallize properly.Yet, while problems that occur in the cGMP suite can be resolved over time, they can come at a cost much larger than when they’re found in the kilo lab where less raw materials are affected. To reduce the risk of late-phase surprises, some experts recommend that additional screening efforts in early development can smooth the pathway in later development stages.
4. Analytical challenges. When a manufacturer qualifies an analytical method, it is assessing that it is suitable for its intended purpose. It compares specific samples of the compound to a standard one to test its reproducibility. Many companies choose to conduct this process early in pre-clinical stages in order to determine the feasibility of the method for the NCE.

While there are endless curveballs that are thrown in the NCE development process, perhaps one of the most important strategies is to work with an experienced CDMO, that is equipped to handle the surprises that can arise. This means a CDMO with cGMP-level labs, plants, equipment and scientists who recognize that while each molecule is unique, there are standard best practices that can applied to enable the best outcome.

Given the volatile nature of NCEs, another key best practice is collaboration and communication. CDMOs and their sponsors must work together to quickly address issues proactively.

New Chemical Entities are just that – new.  Working with a trusted CDMO to bring your NCE to the market can save valuable time, save costs and successfully deliver a critical ingredient to the populations that need it the most.

About the Author

Ed is the President and CEO of PCI Synthesis (PCI), he serves as a co-chair of the New England CRO/CMO Council and sits on the Industrial Advisory Board for the Department of Chemical Engineering at UMass, Amherst. Ed is also a long standing member of the American Chemical Society and advises the Bulk Pharmaceutical Task Force of the Society of Chemical Manufacturer’s and Affiliates (SOCMA).

Do you have questions? Talk to Ed.