Skip links

505(b)(2) CMC Basics: Aligning Chemistry, Manufacturing, and Controls with Clinical Trials

Aligning Chemistry, Manufacturing, and Controls with Clinical Trials

Nine times out of ten, a sponsor approaches their 505(b)(2) drug development process without a clear plan for Chemistry, Manufacturing, and Controls (CMC). What does that do to a development plan? When a 505(b)(2) drug does not have a defined CMC strategy from the beginning, the entire development timeline is in jeopardy.

There are several differences in the CMC requirements for an IND meant for Phase 1 clinical investigations versus Phase 2 or 3 clinical investigations. The CMC development plan is often assumed to be the easiest piece of the puzzle, but many times ends up being the rate-limiting factor to getting a clinical investigation started or to a successful submission of an IND. This has many implications, which should be considered, especially with a 505(b)(2) drug development program, and can have a substantial influence on the overall product development timeline and costs. Optimizing the development path is best accomplished with phase-appropriate CMC development strategies.

Deficiencies in IND CMC sections: Avoiding Clinical Hold

The FDA recognizes that the formulation, analytical procedures, and manufacturing processes for the drug substance and product are being refined and improved throughout the development program, but also expects that the CMC development parallels the clinical investigations. In other words, the product, and thus the CMC, must be at the to-be-marketed stage and not changed during later phases of development (as is often the case with 505(b)(1) drugs in development).

A couple of FDA regulations contain the general principals and content requirements for an IND: 21 CFR 312.22 and 312.23. Included below are a few excerpts which set the tone for this discussion.

  • 21 CFR 312.22(a) “The FDA’s primary objectives in reviewing an IND are, in all phases to assure the safety and rights of subjects, and, in Phase 2 and 3, to help assure that the quality of the scientific evaluation of drugs is adequate to permit an evaluation of the drug’s effectiveness and safety.”
  • 21 CFR 312.23(a)(7)(i) “ …Although in each phase of the investigation sufficient information is required…to assure the proper identification, quality, purity, and strength of the investigational drug, the amount of information needed to make that assurance will vary with the phase of the investigation, the dosage form, and the amount of information otherwise available.”

In essence, CMC requirements differ in what the agency expects to see in the IND depending on the phase of study, study population, route of administration, duration of study, number of subjects, and the available scientific information. The CMC information should be commensurate with the type or phase of clinical investigation. This is where a potential issue may arise during a 505(b)(2) drug development program.

For a 505(b)(2), the active drug moiety has previously been studied in human subjects and thus the initial clinical investigation represents a pivotal study (a study upon which the NDA will rely for key label information) for the development program and thus requires more comprehensive IND information. In many instances such as this, the CMC program can be a rate limiting factor in bringing a new drug therapy to market and thus should be given due consideration when mapping out a development program, from the beginning.

CMC Requirements for a Phase 1

In general, Phase 1 studies are closely monitored and meant to introduce a new drug into human subjects. For Phase 1 studies, the main focus of the required CMC information is safety from the perspective of the risk to the patient. The July 2008 Guidance for Industry: CGMP for Phase 1 Investigational Drugs is intended to assist sponsors in ensuring appropriate drug quality for clinical trial material without impeding drug development efforts.

CMC Requirements for a Phase 2/3 Clinical Investigation

For Phase 2 and 3 investigations, safety concerns are equally as important. However, more detailed data is required in the IND to evaluate the quality of the proposed clinical investigations from a CMC perspective. Recommendations on the content of a Phase 2 or 3 IND CMC submission can be found in the May 2003 Guidance for Industry: INDs for Phase 2 and Phase 3 Studies.  Typically phase 3 studies are what would be called pivotal studies and require that the clinical trial material represent the proposed commercial product.

The Importance of CMC for 505(b)(2)

For a 505(b)(2) that is referencing a listed drug the sponsor typically is required to conduct a bridging study, usually a pharmacokinetics (PK) study. Even though PK studies are typically considered Phase 1, it is a pivotal study and the CMC information needed to support this study should be at the to-be marketed stage to facilitate bridging to the listed drug.  Most often the API CMC information is already at a phase 3 level if there is an up-to-date drug master file filed with the FDA. Critical information needed at this stage include the impurity profiles for both the API and drug product.  These must be known to assure bridging to available known toxicology data.  This CMC information aligns more closely with the data needed for a Phase 2/3 investigation versus a Phase 1.

The Importance of CMC Strategy

Typically a CMC development timeline can require 1.5 to 3 years depending on the complexities of the target drug product and the maturity of the supportive documentation. The CMC development timeline should align with the timelines for the various clinical development phases throughout the program.  Often the CMC requirements for a 505(b)(2), specifically the stability assessment, become critical path tasks on the submission timeline so initiating them early is important. A well thought-out CMC strategy is essential to maintain the timeline for any drug development program. Due to the potentially compressed timing of a 505(b)(2) drug development program, the CMC strategy can be a problem if it has not been mapped out early in the project.

It is also important to note that sponsors can discuss what type of CMC information should be submitted for a specific investigational phase with the agency during a Pre-IND, EOP2, Pre-NDA, and even in some cases CMC-specific meetings.  The March 2015 Draft Guidance for Industry: Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products includes information on the meeting types and describes the standardized procedures for formal meetings with the agency.

Premier Consulting specializes in helping sponsors navigate through phase-appropriate CMC development strategies. Contact us for more information.


Kathy Kemme
Associate Director of CMC Services