Blog Post

CMC Activities for a 505(b)(2) Development Program

June 30, 2021

As discussed in earlier posts, a 505(b)(2) New Drug Application (NDA) is an abbreviated approval pathway. According to the 1999 FDA draft guidance “Applications Covered by Section 505(b)(2)” this pathway is commonly used for approved drugs that have undergone any one or more of the following alterations:

  • Dosage form
  • Strength
  • Route of administration
  • Salt or form of an active ingredient
  • Dosing regimen
  • Formulation (different quality or quantity of excipients)
  • Combination product (substitution of an active ingredient in a combination product or creation of a new combination product in which the active ingredients were previously approved separately)

A sponsor should submit a marketing application via this pathway when at least some of the information required for approval originates from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use.

To support a 505(b)(2) application that involves any of the changes listed above, the Chemistry and Manufacturing Controls (CMC) development team should be involved early in the project. As the name suggests, this team develops the processes and analytical methods used to manufacture drug substance(s) and drug product(s) and is ultimately responsible for providing the data needed to demonstrate identity, strength, purity, potency, and stability of the material. For a 505(b)(2) development program, the CMC team develops and implements the proposed changes to the drug substance(s) or drug product(s) and manufactures the materials to support any stability, bridging, nonclinical, or clinical studies that may be necessary to support the marketing application.

As with a 505(b)(1) NDA submission, Module 3 of a 505(b)(2) submission must include the following information for drug substance and drug product to demonstrate that all quality standards are met for the new product:


Drug Substance Drug Product
·        Physical and chemical characteristics ·        Formulation components and composition
·        Manufacturer ·        Specification for each component
·        Synthetic and purification process ·        Manufacturer
·        Process controls ·        Description of manufacturing and packaging process
·        Specifications ·        In-process controls
·        Stability ·        Specifications for final product
·        Stability

Frequently for 505(b)(2) NDA submissions, the drug substance is unchanged from the listed drug, and the sponsor must identify a supplier who is able to manufacture drug substance of comparable quality to the listed drug; this often entails reverse engineering a synthetic route. The new supplier may document manufacturing information in a Drug Master File (DMF) and reference the DMF in Section 3.2.S of Module 3 to supply drug substance information in the submission. If a DMF is not referenced in the 505(b)(2) submission, the sponsor is required to provide the information listed above for the drug substance.

Often in a 505(b)(2) NDA, much of the CMC drug product information from the listed drug or published literature is not applicable to the new drug product and a complete 3.2.P section will be required. This section will house the information listed above and will also include the full product development history and batch analysis tables for the new drug product formulation.

To avoid delays when submitting a 505(b)(2) NDA, the CMC activities are a key area of focus and must be a major priority during the development of the project timeline. Since nonclinical and clinical development can often move more quickly for a typical 505(b)(2) development program, CMC activities often become rate-limiting to the execution of the development program and submission of the NDA. As with a 505(b)(1) NDA, the CMC stability requirement will have the largest impact on a project’s timeline. According to ICH Q1A guidelines, a minimum of 12 months of stability at the long-term storage conditions and six months at the accelerated conditions for three pilot batches in the proposed commercial packaging must be included in the marketing application. For drugs with a new dosage form, ICH Q1C does allow for filing with six months of stability data at the proposed long-term condition, but the sponsor must justify this decision. Strategies may be developed to finalize the manufacturing scale and process as well as the proposed container closure early to minimize the impact of the stability requirements.

In summary, while a 505(b)(2) NDA can help a drug get to market faster, the time to complete the CMC activities cannot be overlooked, and the quality data package that is required in the marketing application must be incorporated in the overall project timeline. Rho has an extensive history in supporting clients with their drug development programs and can help devise an appropriate strategy for a 505(b)(2) submission.

Aimee Weber, Associate Director, CMC Regulatory, has more than 20 years of experience in the pharmaceutical industry, specializing in Chemistry, Manufacturing and Controls (CMC) for both drug product and drug substance. She has contributed to the development of a diverse range of drug substances covering multiple therapeutic areas and drug product formulation types, with extensive experience with semi-solid dermatological products. Ms. Weber is responsible for working with clients, providing advice for CMC regulatory strategy and authoring sections of Module 3 for all stages of clinical development. She is well versed in eCTD format and has authored a variety of CMC submissions, including INDs, IMPDs, Briefing Books and has been involved with two marketing applications. Ms. Weber earned her Bachelors of Science in Chemistry from Hope College in 1999.