Excipients group seeks GDUFA III participation

Increasing the timely, safe, and cost-effective availability of generic drugs requires that excipient issues be addressed as an integral part of the process, said Priscilla Zawislak, Immediate Past-Chair of International Pharmaceutical Excipients Council (IPEC)-Americas.
 
Zawislak, speaking at the 21 June 2020 public hearing kicking off the reauthorization process for the third Generic Drug Fees User Amendments (GDUFA III), said that excipient manufacturers are also asking for improvements in communication with FDA on excipient issues, and for formal inclusion of IPEC-Americas in the ongoing GDUFA discussions.
 
“Excipient issues need to be incorporated into the GDUFA agreements in a way that will benefit FDA, industry and the patient. We request the opportunity to help ensure that the data in the [Inactive Ingreident Database] are complete, consistent, accurate and maintained as such throughout the data lifecycle,” said Zawislak. (RELATED: FDA kicks off GDUFA III reauthorization process, Regulatory Focus, 21 July 2020)
 
Zawislak said that IPEC-Americas would also like to see GDUFA III tackle some additional policy and integrity issues related to the Inactive Ingredient Database (IID) that were not addressed under GDUFA II.
 
“We continue to be concerned with data integrity and traceability of changes to records made in the Inactive Ingredient Database,” said Zawislak. In addition to the current “clean-up” activities happening under GDUFA II, Zawislak said that FDA reviewers should be looking at a way to increase the effectiveness and efficiency of the review process for IID.
 
The excipients industry would also like to see alignment “between the global substance registration system, the IID, and nomenclature use,” she said.
 
The rapidly developing complex generic landscape heightens the urgency to address excipient and IID issues, said Zawislak, citing combination products, transdermal applications, and excipients being used in medical devices as examples. “Currently, records in the IID are inconsistent, and there is no FDA policy available for the generic drug manufacturer to review and evaluate precedents for an excipient relative to these types of dosage forms.
 
“Considering the rapid expansion of focus on complex generics, it is critical for FDA to provide clarity” on these issues, she said.
 
The absence of a clear and established regulatory pathway for novel excipients which are not novel chemical entities is another problem faced by excipient manufacturers, said Zawislak, noting that there is a “lack of clarity” about how information in the IID should be used in this instance.
 
“We are aware that some FDA reviewers have stated that the drug product formulator should use an excipient with an established safety profile,” by looking to FDA-approved products that have the same route of administration and level of use. “We call this formulation by IID,” she said.
 
However, Zawislak said that the risk is that “companies may formulate suboptimal drug products in order to avoid perceived regulatory risk” when they feel constrained in excipient choice. “We believe that this current approach is a deterrent to generic product innovation, impedes the development of new drugs, is counter to FDA policy of using risk assessment principles, and does not enhance patient safety,” she said.
 
IPEC-Americas is advocating for the development of an excipient guidance document that defines requirements for good bridging studies and develops a policy and training for reviewers for when – and how --  a “good bridging study might be used to support a submission,” according to Zawislak. Such guidance, she said, would improve the quality of submission and would boost first-time approval rates, ultimately making generics available at lower cost and in timelier fashion.
 
On a related point, Zawislak addressed the FDA definition of “novel excipient.” Currently, the agency calls an excipient novel if it has a material or composition that has not been previously used in an approved product in the US and is not listed in the IID for the intended route or level of administration. IPEC-Americas, said Zawislak, seeks a differentiation between new chemical entities and those which currently are classified as “novel” based solely on “a slightly higher level of use, a chemical modification, or a different route of product delivery.” Where an excipient has data supporting safe use for a related use and level of exposure, she said, the “novel” designation may not be appropriate.

“This type of system would give drug developers greater confidence to include novel excipients into products and facilitate innovation,” she said.   
 
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