In comments submitted in October 2013 to the US Food and Drug Administration (FDA), the Generic Pharmaceutical Association (GPhA) said its member companies need additional clarity on a recent guidance document published by FDA, Abbreviated New Drug Applications; Stability Testing of Drug Substances and Products: Questions and Answers.
Stability testing is necessary to obtain approval for an abbreviated new drug application (ANDA), more commonly known as a generic drug application. Under Section 505(j) of the Federal Food, Drug and Cosmetic Act, companies not only must show that a follow-on product is bioequivalent to a reference-listed drug in FDA's Orange Book, but must also show that it has the same ability to hold its characteristics and potency over time.
In September 2012, FDA released a guidance document on the subject, calling on sponsors to adhere to ICH's Q1A, B, C, D and E standards for stability testing. "Although the ICH stability guidances were developed by ICH to provide guidance on the information that should be provided in NDAs to ensure the stability of new drug substances and drug products, we believe the recommendations should be applied to ANDAs as well," FDA explained in the guidance.
In August 2013, FDA then published its Q&A guidance on the topic, with a particular interest in answering some of the most common questions about the President's Emergency Plan for AIDS Relief (PEPFAR), the timing of stability testing studies, and the definitions of several regularly used terms.
New Answers Lead to New Questions
But even having answered 29 questions, FDA's Q&A guidance didn't answer or give sufficient clarity to enough, GPhA said in its comments.
In some cases, the language used by FDA in its answers generated entirely new questions. For example, Q3(ii) sought to clarify when intermediate stability studies needed to begin. FDA had recommended starting all stability testing-accelerated, intermediate and long-term-at the same time so as to ensure that all data are available at the time of submission "if needed."
However, industry said this raised a new question: "If a firm learns from development studies that the product cannot withstand accelerated stability condition, but it meets all quality attributes at intermediate stability conditions, then is it acceptable to keep only exhibit batches on intermediate stability and CRT condition (and not on accelerated stability)?"
Similarly, if accelerated approval conditions fail, industry wanted to know how much intermediate data would be needed to support a 24-month expiry date. Industry also recommended removing a requirement that six months of accelerated approval data be generated, saying if a study fails through three months, it should not be necessary.
Elsewhere, GPhA asked if FDA recommendations to keep pilot scale batches for one year post-approval applied to the entire batch, or just a subset of the entire batch. Industry was similarly confused as to whether this timing was set into motion at the time of a tentative approval, or if it required full approval of the ANDA to kick in.
In all, GPhA's response to FDA contains dozens of highly specific questions directed at nearly half of all answers provided by FDA in its guidance, but stops short of offering the sort of targeted criticism of the guidance that trade groups often level at the agency. GPhA clarified that it was "providing comment for only those questions for which our member companies have specific questions and recommendations."
Generic Pharmaceutical Association (GPhA) - Comment