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Looking for Clarification on Reporting Post-Approval Changes to a Drug Substance to the FDA? You are in Luck.

This week the FDA released a new draft Guidance for Industry entitled “Post-approval Changes to Drug Substances” as part of the FDA’s commitment to the reauthorization of the Generic Drug User Fee Amendments (GDUFA II).

The new draft Guidance fills an important void as the existing Guidance for Industry: Q11 Development and Manufacture of Drug Substances (2012) barely touches on post-approval changes and the Guidance for Industry: Immediate Release Solid Oral Dosage Forms, Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation (1995; also known as the SUPAC Guidance) is more general and is limited to solid oral dosage forms. The new Guidance provides more specific information on demonstrating equivalence between the approved and the proposed drug substance, and supports a risk-based assessment to help guide the decision-making process.

The new Guidance clearly outlines the parameters for determining the impact of postapproval changes, the subsequent process for informing the FDA, and the documentation that drug substance manufacturers or Drug Master File (DMF) holders must submit when planning or implementing the changes.

Changes Covered by the Guidance

The Postapproval Changes to Drug Substances Guidance (referred to as the Guidance from here on) is directed at sponsors that wish to make changes to the drug substance listed in their approved NDA, ANDA, New Animal Drug Application (NADA), abbreviated NADA, or holders of a Drug Master File (DMF) or Veterinary Master File (VMF). Sponsors wishing to make changes to the drug substance in a complex generic product, or a biologic or drug substance approved via a Biologics Licensing Application (BLA), are directed to other appropriate guidances.

The Guidance applies to synthetic drugs; not to peptides, oligonucleotides, radiopharmaceuticals, botanically-sourced drugs, or drugs that are manufactured via non-synthetic steps such as fermentation.

The type of changes covered by the Guidance include:

  • Facility, scale, and equipment changes associated with all steps of drug substance manufacturing.
  • Specification changes to starting materials, raw materials, intermediates, and the unfinished and final drug substance.
  • Synthetic manufacturing process changes.
  • Changes in the source of the drug substance.
  • Changes to the container closure system for the drug substance.

Determining the Reporting Category

The first step in the process is for the application or DMF/VMF holder to determine the reporting category based on the potential risk for the change to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product. This is to be determined based on the Code of Federal Regulations (21 CFR 314.70, 314.81, and/or 514.8), the Guidance, and other guidances listed in Section XII Reporting Category, in that order.

The three categories include:

  • major changes: require submission of a prior approval supplement (PAS)
  • moderate changes: require submission of a change being effected (CBE) in 0 or 30 days supplement)
  • changes to be described in an annual report.

Process for Submitting Changes

Changes to a DMF must be submitted as an amendment to the DMF. The DMF holder must notify all persons authorized to reference the DMF (holders of the approved applications). The application holder must then determine the reporting category and notify the FDA as appropriate if the changes are outside of the variations approved in the application.

If the drug substance information is contained in an application, moderate or major changes must be submitted as a supplement to the approved application (Section 3.2.S). In some cases, the changes must be reported as both an amendment to one or more DMFs and as a supplement to an application, by the respective parties, if the information in each will need to be changed.

Assessment of Risk

The Guidance provides ample advice on determining the risk that a change may result in an adverse effect on quality, either in the physical properties of the drug substance or in the level or nature of impurities present, and, in some cases, to the bioequivalence or safety profile of the drug. Clear examples of factors to consider when conducting a risk assessment on a change to the drug substance are provided.

Assessment of Change

Drug Substance: in most cases, DMF or application holders will need to compare three consecutive pilot or commercial scale batches of pre- and post-modification material to assess the impact of the change on the quality.

The assessment may include:

  • A comparison of impurities in pre- and post-modification intermediates, the unfinished drug substance, and/or the drug substance.
  • A comparison of the drug substance’s physical properties before and after modification. This may be more or less relevant depending on the dosage form (Table 1 in the Guidance) and the change (Table 2 of the Guidance).
  • Drug substance stability data.

Depending on the type of change, more tests may be required. In some cases, a rationale can be provided for performing the tests on fewer batches.

Drug Product: if equivalence of the drug substance cannot be established, and the drug substance physical properties can affect manufacturability or performance of the drug product, it may be necessary to assess the drug product made with the post-modification drug substance.

Documentation to Submit

The amount of data submitted should reflect the reporting category and the outcome of the risk assessment. When reporting the changes to the FDA, the holder of the application or DMF should include the following for the drug substance. If required, the application holder should also submit the following for the drug product.

  • the risk assessment
  • a description of the change
  • comparison of the impurity profile pre- and post-modification (or dissolution and analytical procedure data for drug product)
  • stability data/commitments
  • changes to specification for raw materials, intermediates, and drug substances if applicable, including rationale, description of change, method description, etc.
  • certificates of analysis (COAs) from 3 consecutive batches

The Guidance continues to provide detailed information on what to submit in various situations, and with detailed examples.


Premier Consulting welcomes the new draft guidance and the clarification it brings to previously ambiguous territory. Contact our chemistry, manufacturing, and controls (CMC) experts to determine the tests and documentation that are required for planned changes to your drug substance or drug product, or any CMC related questions that you may have.


Angela Drew, PhD
Product Ideation Consultant