One of the main causes of Refusal to File / Receive actions by the US FDA is due to inadequate Chemistry, Manufacturing, and Controls (CMC) data. This missing data relates to formulation issues, incomplete stability data, and inactive ingredients listed above the limits found in the Inactive Ingredients Database without appropriate supportive data. A drug under development for approval via the 505(b)(2) pathway must link the safety and efficacy of the Listed Drug (LD) to the proposed drug product. Specifically, the 505(b)(2) application must include sufficient data to demonstrate that the proposed drug product meets the statutory approval standard for safety and effectiveness. In addition, to gain CMC right of reference, a bridging clinical study may also be required.
Bridging and 505(b)(2)
So, what is meant by a bridging study for CMC purposes? During the 505(b)(2) drug development process, a company will often change the formulation, components, or active pharmaceutical ingredient (API). A review of the evolution of the formulation and the data supporting the comparability of the different formulations provides the basis for the Pharmaceutical Development section of the submission document. The resultant sum of these changes must be evaluated for impact on the safety and efficacy of the proposed drug product to gain approval (see 21 CFR 314.54(a)).
Let’s look at some examples where we may need to do additional pre-clinical or clinical studies to show that the proposed changes don’t alter the conclusions reached by the phase 1 pharmacokinetic bridging study.
CMC and API
API supplies may be interchangeable, but frequently they are not. A good example is an active raw material that can be extracted from plant origins, or alternatively, can be chemically synthesized. The ‘same’ material from these different sources would likely present different impurity profiles. Toxicological qualification of the worst-case impurity profile is a pivotal non-clinical study. It is not only good practice to include the majority of the representative impurities in the non-clinical toxicology studies, it is a requirement that FDA has addressed (guidance Q3A – Impurities in New Drug Substances).
A bridging study can be done in the lab using, for example, dissolution testing. Consider a USP excipient change, perhaps due to change in vendor. It is possible that even though an excipient from different suppliers meet the USP requirements, each may perform differently during the manufacture of the product or on stability, providing an unwelcome surprise. This performance difference can be traced to any number of reasons, e.g. residual solvent variations, changes in particle size distributions, different crystal morphology, etc.
When a change is made during development, documentation of the change and evaluation of the impact will lead to a decision whether this will influence the product quality, most typically apparent in the bioavailability. This evaluation should be protocol driven. If a major change is proposed, a determination should be made by the scientific team as to the most critical performance characteristic to study. A comparability protocol can be written and submitted in advance of the change to FDA ultimately shortening the approval time for changes to an already-approved product. The resulting (before and after) products can be studied side-by-side in a well-controlled dissolution experiment which can address the bioequivalence and the comparative bioavailability. If the dissolution experiments are inconclusive, an in vivo animal model bridging study may be required to verify that the efficacy or safety of the product is consistent with what has been produced throughout the development program.
CMC and Formulation Changes
If a sponsor has had several different formulations during the development program and has not performed a bridging study, then questions may arise as to the validity of data collected before changing. The FDA will request some bridge, before they can accept those early data. This can be difficult to reproduce if enough data were not collected during the early phases of development. If, for example, the vendor for the API source is out of business it would be difficult to demonstrate equivalence to a new vendors’ material. Likewise, changes to the manufacturing process due to unforeseen circumstances may interfere with the ability to demonstrate equivalency between processes. Any time there is a change in the CMC, proving consistency becomes more difficult. There are many reasons why consistency might be difficult to prove if a sponsor waits until the agency asks for it.
Taking care to review the implications of changes during the development process and incorporate prudent comparability protocols at the right point in the program can answer most questions and address issues before they become problems. From a quality management standpoint, these issues should be addressed by a robust Change Control program. In every case, working to ensure consistency in every aspect of CMC is needed to provide a coherent and approvable Pharmaceutical Development Summary for the proposed drug product.
Premier Consulting’s in-house CMC experts specialize in bridging data for 505(b)(2) drug candidates to that of the approved listed drug and can help get your development program back on track or address issues before they start. To learn more, contact us.
Robert Kessler, PhD
Senior Director of Analytical Development