Regulatory Considerations for Controlled Correspondence Related to Generic Drug Chemistry

Discussion and results On average, the agency receives approximately 1200 correspondences yearly. Approximately 5-10% are related to generic-drug chemistry. The number of chemistry-related correspondences has increased steadily since 2011, as shown in Figure 1

. Topics in these correspondences can be loosely grouped into 11 categories:

  • Combination products
  • Container closure system
  • Dissolution
  • Formulation
  • Inactive ingredients
  • Overage
  • Stability
  • Specifications
  • 505(j) eligibility
  • Post-approval changes
  • Pre-approval changes.

Each correspondence was assigned to one category, and the number of correspondences under each category was counted and summarized in Figure 2. Categories with the highest number of counts include formulation, stability, specifications, and post-approval changes.

Figure 2: Number of chemistry-related controlled correspondences (CC) per category.

Formulation is a broad category, but generally consists of inquiries about API-related topics such as allowable particle size, salt stoichiometry, or synthetic route deviations from the reference listed drug (RLD); the presentation of the dosage form; and other allowable deviations from the RLD.

The specifications, post-approval changes, and stability categories were broken down into sub-categories to further elucidate trends.

Specifications is a broad topic, which includes questions related to residual solvents, identity, limits, drug master file (DMF), test method, validation, and impurity (see Figure 3A). While the counts in many of the subcategories were distributed relatively evenly, test method and impurity stood out as major topics. Test method questions were highly varied and case-specific. These questions sought specific recommendations on the procedure and/or data requirements for stability testing; API/excipient characterization and compatibility; in-process testing; quality requirements; and ANDA submission data requirements.

Figure 3A: Breakdown of the specifications categories. CC is controlled correspondence.

Inquiries about residual solvents or impurities generally requested advice on the limits or the types of solvents/impurities found with a particular API. The limits category catches all other inquiries regarding limits that are not pertaining to residual solvents or impurities; these questions largely requested advice on the setting of assay limits for the API.

Inquiries regarding post-approval changes (see Figure 3B) revolved almost exclusively around questions about which post-approval reporting category was most appropriate, followed by requests for advice on any other information or data that should be filed with the supplement(s). Questions in this category will no longer be considered as controlled correspondence; the draft Guidance for Industry: Controlled Correspondence Related to Generic Drug Development (August 2014) considers any questions related to a pending or approved ANDA as a review issue and outside the scope of controlled correspondence (1). However, the agency is trying to establish some mechanism to address general questions for approved ANDAs during the post-approval phase.

Figure 3B: Breakdown of post-approval changes. CC is controlled correspondence.

Stability questions were divided into subcategories (see Figure 3C) and pertained to requirements for batch size and requests for approval of bracketing or matrixing protocols. Batch number questions generally seek to clarify how many primary stability batches are required for supporting the ANDA submission given the requirements set forth in the June 2013 Guidance for Industry, ANDAs: Stability Testing of Drug Substances and Products (5). Because the release of this guidance and the subsequent May 2014 Guidance for Industry, ANDAs: Stability Testing of Drug Substances and Products Questions and Answers (6) generated many questions and represents a relatively major shift in FDA’s approach, further analysis of these controlled correspondences will be elaborated in a future publication.

Figure 3C: Breakdown of stability categories. CC is controlled correspondence

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