On the 10th of September 2018 FDA released a new draft named “Postapproval Changes to Drug Substances” containing 38 pages (including 2 Appendices) which provides the information regarding the changes to the Drug Substance (DS) manufacturing process during an application’s post-approval period. Therefore, manufactures of Active Pharmaceutical Ingredients who want to implement these kinds of changes now need to take into account this draft.
This document was published as a part of the reauthorization of the Generic Drug User Fee Amendments (GDUFA II). The guidance has the recommendations for the holders of approved new drug applications, Generics (ANDAs), new animal drug applications, abbreviated new animal drug applications, and holders of drug master files and veterinary master files who plan to make amendments in the DS manufacturing process during the application’s post-approval period. However, FDA indicated that this guidance cannot be applied 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.”
To summarize, the document gives the information on the following alterations:
- Premises, scale and equipment changes which affect any step of DS manufacturing process;
- Specification changes to starting materials, raw materials, intermediates and the unfinished and final DS;
- Synthetic manufacturing process alterations;
- Changes in the source of DS;
- Changes of the DS package.
It is also necessary to mention that the draft guidance states that any changes in the final stages of DS manufacturing process are generally considered as “more likely to have an adverse impact on the quality of the drug substance and, consequently, on the drug product”. Hence, the manufacturer has to submit a Risk Assessment of these amendments for FDA review
Thus, providing DS equivalence cannot be proved and the DS physical properties may influence producibility and performance of the Drug Product, application holders must evaluate the Drug Product manufactured using the DS which was produced under modified conditions before dispensing the Drug Product.