Pitfalls of Chemistry, Manufacturing, and Controls in Investigational New Drug Preparation

Developing an investigational new drug (IND) application is a big milestone for organizations, especially small companies bringing their first drug to market in the U.S. Too often, though, the chemistry, manufacturing, and controls (CMC) aspect of the IND are not fully considered until it is too late, resulting in a delayed IND submission or even a clinical hold letter from the Food & Drug Administration (FDA). To understand more about how these roadblocks may impact an IND, this blog outlines three common CMC pitfalls.

CMC Activities Did Not Start Soon Enough

Many times, small research-oriented companies moving toward their first IND do not adequately consider the requirements for manufacturing and testing clinical trial materials (CTM). To file an IND, an organization must produce batches of drug substance and drug product of the actual material to be used in the clinic study.  Analytical development scientists can use analytic methods that are validated and fit-for-purpose to test the CTM. The batches of drug substance and drug product need to be placed on stability, and, at a minimum, one month of stability data must be included in the IND upon submission. Technical batches or data used for toxicology studies are not sufficient to satisfy this requirement. Generally speaking, the CTM supply strategy should be in place, and execution should start 9-12 months prior to filing an IND.

No Anticipation of Good Manufacturing Practices for the CTM

Manufacturing sites registered with the FDA to operate pharma GMP regulations can produce CTM for clinical studies. While manufacturers are located anywhere in the world, if the trial is in the U.S., they must be registered with the FDA in order to produce CTM. Sometimes, small companies will attempt to use material made in their own or others’ non-registered laboratories. Even though this material is suitable for nonclinical studies, it is not acceptable for use in human clinical trials.

Another pitfall observed is that the drug substance and drug product are manufactured under food grade or dietary supplement grade Good Manufacturing Practices (GMPs). The FDA may accept this concept in exceptional cases, not routinely. If this route is desired, it is recommended to obtain FDA acceptance of this practice be discussed in a pre-IND meeting rather than to propose this concept for the first time when the IND is submitted.

Good Laboratory Practice Toxicology Lots are Too Clean

Drug developers sometimes strive to make the best, most pure material possible for use in the good laboratory practice (GLP) toxicology studies. In the long term, this is not a good idea. The GLP toxicology studies not only support the safety of the active ingredient in animal and human settings but also the qualification of impurities up to the level that is seen in the toxicology material. To this end, “dirty is good” is an ideal to consider in order to qualify impurities. There is such a thing as “too dirty,” but some impurities are a good thing in a toxicology study.

Advarra’s Regulatory Center of Excellence CMC experts can plan and assist organizations to avoid these pitfalls and guide their new products through the IND approval process with minimum issues, beginning their clinical trial as soon as possible. Contact us today to get started.

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