Starting at the crack of dawn for us west coasters, today’s meeting kicked off with three presentations on application issues: mid-cycle meeting overview; information to include in cover letters; and application communications – quality perspectives.  Lots of information was presented and highlights are discussed below.

Mid-cycle reviews are reserved for complex generics and may also be granted for Competitive Generic Therapy (CGT) products.  Meetings are only thirty minutes in length so use your time wisely.  Usually, there is only time to cover the FDA’s agenda items, but you may be able to slip in a question or two that may or may not be addressed depending on whether the FDA participants are prepared to respond to your specific questions.  The mid-cycle meeting is to “convey, to applicants, key issues or concerns that were identified during the Abbreviated New Drug Application (ANDA) review” and for the FDA to clarify questions about the submission.  Timelines for meeting scheduling and agenda were addressed, as well as “what” to expect in the meeting notice letter from the FDA.

Some metrics regarding the numbers of mid-cycle review meetings were presented for both complex products and CGT products.  The FDA noted that, in 2018, the first year of the program, there were five meetings scheduled for complex products (CPs), in 2019, there were ten meetings for CPs and two for CGT products, and, in 2020, the numbers were much higher, twenty-one meetings for CPs and fifteen for CGTs.

The cover-letter presentation was very detailed and comprehensive, and I believe the most important information actually was a description of the commonly omitted information that could cause the FDA issues.  Some of these items include:

  • MMA/Verification Statement [21 CFR 314.96(d)(1)]
  • Priority Requests on every resubmission after action letter is received even if priority has been previously granted
  • Unsolicited Information (assure the identification of the new information is identified)
  • New or revised patent certification or litigation updates
  • Major Amendment Information – not explaining whether there are new batches, changes in facilities, DMF changes, etc.

Best practices were also outlined for preparation of the cover letter.  For example, keep important information in the beginning of a long cover letter to allow the FDA to easily recognize which disciplines need to review the submission

The third presentation provided timeline expectations for ANDA review touchpoints; that is, when to expect information requests, discipline review letters, and complete response letters.  The audience was reminded to submit complete and timely responses to IR and DRL communications.  Incomplete responses and those that do not fully address all questions will not be considered for review and untimely submissions may not be considered if revised timelines or extensions are not requested.  The FDA indicated that not all extensions for submission of responses will be granted, especially depending on where the application is in the review cycle.

Emerging technologies for manufacturing and testing provide a challenge to the industry and the FDA but the rewards can be improved efficiency in manufacturing and cost saving to industry.  Various manufacturing techniques, such as end-to-end manufacturing, continuous manufacturing, 3D printing, and continuous aseptic spray drying, were alluded to, among others.  While the FDA has knowledge of many of the emerging technologies, some are brand spanking new and the Agency will have to learn along with the applicant.

Dr. Rachael Dunn from the St. Louis Office of Testing and Research (OTR) in the Office of Product Quality Lab discussed how the OTR interacts with the review divisions, Office of Compliance, and other FDA organizations.  Some of the activities of the lab include surveillance testing, development of methods for testing, analysis, and characterization of complex products, such as peptides. They are also involved in: standards, guidance, and policy development; pharmaceutical quality surveillance; quality assessment of regulatory submissions; and response to public health issues.  OTR also participates in developing in vitro approaches for characterizing complex formulations and developing and evaluating biorelevant mouth-throat models as in vitro methods for inhalation products for more accurate and relevant particle deposition techniques.

There were two presentations by OPQ representative covering extractable and leachable (E/L) studies, one on the studies required for container-closure systems and one on E/L studies required in the manufacturing/processing systems (e.g., filters, tubing, and relevant equipment components).  Key takeaway points include using appropriate solvent systems, having validated methods, and providing justification for use of same, following appropriate USP methods, being sure to use correct analytical evaluation threshold (AET)/safety concern threshold (SCT), and, if exceeded, be certain to contain appropriate justification, including appropriate toxicology support.

Busy morning for sure.  We will provide a brief summary of the afternoon session later in the day.