FDA´s draft Guidance on Post-approval Changes to APIs

Manufacturers of APIs (Active Pharmaceutical Ingredients) who want to make changes to the Drug Substance (DS) manufacturing process during an application's post-approval period should consult U.S. FDA´s (Food and Drug Administration) new draft guidance released on September 10, 2018.

The 38-page draft (including 2 Appendices) entitled "Postapproval Changes to Drug Substances" has been completed as part of the commitment to the reauthorization of the Generic Drug User Fee Amendments (GDUFA II). The document provides recommendations to holders of approved new drug applications (NDAs), Generics (abbreviated new drug applications, ANDAs), new animal drug applications (NADAs), abbreviated new animal drug applications (ANADAs), and holders of drug master files (DMFs) and veterinary master files (VMFs) who may want to make a change to the drug substance manufacturing process during the drug product application´s postapproval period. However, the draft notes that it does not address postapproval changes to "peptides, oligonucleotides, radiopharmaceuticals; or drug substances isolated from natural sources or produced by procedures involving biotechnology; or nonsynthetic steps (such as fermentation) for semisynthetic drug substances."

The draft guidance covers the following changes:

  • 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 drug substance; and
  • Changes to the container closure system of the drug substance.

Established Conditions
The published guideline contains the concept of Established Conditions (ECs) which is in-line with the concepts presented in the current ICH Q12 draft guideline Pharmaceutical Product Lifecycle Management. Application holders must notify FDA about changes to ECs in approved applications beyond the variations already provided for in their applications. FDA’s regulations identify three broad reporting categories:

  • Major changes (changes that require submission of a prior approval supplement (PAS));
  • Moderate changes (changes that require submission of a changes being effected in 30 days (CBE-30) supplement or a changes being effected (CBE-0) supplement);
  • Changes that must be reported in an annual report.

The reporting category for a change is 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 as these factors may relate to its safety or effectiveness.

Risk Assessment
The document notes that late-stage changes in the drug substance manufacturing process are generally viewed as "more likely to have an adverse impact on the quality of the drug substance and, consequently, on the drug product". The discussion of the change being reported should be accompanied by a Risk Assessment (RA) for FDA review and recommended documentation. The amount of data submitted to justify a change and the type of reporting category chosen should be fully supported by the outcome of the RA. According to FDA, the RA "need not be a lengthy, complex document but should show how the risk was evaluated and explain how the accompanying data demonstrate the risk was addressed or mitigated to support the selected reporting category". The DS documentation should be submitted as an amendment to the referenced master file, or in the DS section in a supplement to the approved application when no master file is referenced. The Drug Product (DP) documentation should be submitted as an annual report or supplement to the approved application depending on the risk associated with the change. 

Change Control is generally understood to be the responsibility of the Quality Control (QC) unit. Effective change control activities are key components of the Pharmaceutical Quality System (PQS). Although the draft guidance does not repeat the concepts and principles explained in the GMP (Good Manufacturing Practice) and ICH guidances, FDA encourages the use of modern pharmaceutical development concepts, Quality Risk Management (QRM), and an effective PQS at all stages of the manufacturing process life cycle.

Responsibility for Reporting
The document states that "the responsibility for reporting the types of changes described in this guidance could lie with a single party or with several parties, depending on whether the drug substance synthesis or processing is described in an application or in one or more master files". However, "the notification to FDA should include reference to the section of this guidance under which the change is made and all pertinent information to ensure the quality of the drug substance and drug product".

Effect on the Drug Product
When, as a result of the change, the DS equivalence cannot be established, and the DS physical properties can affect manufacturability or performance of the DP, application holders must assess the DP made with the post-modification DS before distributing the DP. In such cases a batch of DP should be manufactured to fully evaluate the effect of a change in DS manufacturing. The DP batch may be of reduced size, though usually not less than 10 percent of a normal commercial-scale batch. Release testing and the results of in-process testing should be provided for the DP batch.

Additionally, the document contains two appendices:

  • APPENDIX A (illustrative): Changes to DS manufacture,
  • APPENDIX B: Reporting Categories for additional examples of changes.

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