On September 10, 2018, the FDA issued draft guidance on Postapproval Changes to Drug Substances, with recommendations regarding changes to drug substance manufacturing processes during the postapproval period. The guidance provides general considerations for assessing risk and change to the drug substance and product, as well as recommendations for the types of data to submit when proposing one or more changes in facility, scale, and equipment; specification; manufacturing process; starting materials; and container closure systems.

The guidance indicates that drug substance manufacturers must assess modifications throughout the manufacturing process to determine their associated risks. Risk assessment principles are outlined in the International Council for Harmonisation guidance for industry Q9 Quality Risk Management. Factors to consider in assessing risk may include experience of the facility and personnel involved, complexity of the involved manufacturing steps, physical and chemical stability of the involved material, complexity of the molecule, equivalence of the entire impurity profile, and comparability of physical properties when they may impact product performance or manufacturability.

Drug master file holders and drug substance manufacturers should assess the effects of the proposed manufacturing changes to the drug substance. According to the guidance, this can be done by comparing three consecutive pilot or commercial scale batches of pre- and post-modification material. Evaluating the change may include comparing impurities in intermediates or the drug substance, comparing the drug substance’s physical properties, or examining drug substance stability data. If drug substance equivalence cannot be established and the drug substance’s physical properties can affect manufacturability or performance of the drug product, the application holder must also assess the drug product made with the post-modified drug substance before distributing the product.

In addition to showing how the risk was evaluated, the risk assessment should explain how the accompanying data demonstrate that the risk was addressed or mitigated. Proposed changes should be supported by the documentation recommended in the guidance. Readers are encouraged to read the draft guidance, also available on the FDA’s website.