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By Radhika Rajagopalan

The FDA Generic Drug User Fees Amendment (GDUFA) has entered a relatively matured stage with applicants of Abbreviated New Drug Applications (ANDAs) experiencing a timely review and communications regarding their submissions packet, as well as increasing approval numbers. Thankfully, this means the FDA’s efforts at initiating Guidances, Policy and Procedure guidelines, and instructional webinars to clarify expectations for ANDAs submissions is working. Additionally, the ‘one cycle approval,’ a sought-after award for ANDA applicants, is increasing in numbers. That’s the good news.

However, until an ANDA applicant receives an initial letter from the Agency that the application has been filed for review, uncertainty remains. Complications and delays mount with the receipt of communications such as Refuse to Receive (RTR) letters causing major regulatory setbacks, particularly as the first to file a complete ANDA submission could be eligible for market exclusivity.

The regulatory hurdles for ANDA submissions present real concerns for applicants. Thankfully, an understanding of these challenges so that they may be addressed early on can expedite FDA review and approval, potentially offering the opportunity to create a competitive advantage.

As you prepare your ANDA for submission, ensure you have addressed these five critical areas which commonly create challenges during FDA’s review.

Sourcing API and critical excipients

While some applicants manufacture their own Active Pharmaceutical Ingredient (API), many ANDAs rely on Type II Drug Master File (DMF). Selecting the one (or two) API supplier(s) can be challenging to manufacture exhibit batches, as the source is locked-in for the drug product life cycle, until future supplements can be filed for adding additional sources. Similarly, selecting the vendors for critical excipients, and having a supply chain evaluation/audit mechanism in place to manufacture a consistent quality product is essential. The DMF review does not commence unless an ANDA is filed with a Letter of Authorization, and without proper preparation, the first review almost always results in deficiencies. Navigating synthesis related deficiencies, impurities that should have been addressed, and facility inspection results, continue to add review cycles, and time.

Not utilizing control correspondence mechanism to obtain Agency input in relevant areas

Controlled correspondences are widely used by ANDA applicants prior to ANDA submission attempt. While one should refrain from inundating the Agency with control documents, submitting them for the type of studies needed (when no recommendation is available) should continue. Control questions should not be aimed at asking the Agency for exemptions (such as testing), but rather seek guidance when there is a real issue at hand. The Agency has published a guidance on this topic as well, and use of Controls may negate some pitfalls.

CMC related issues and the compelling case for a through product/process development report

Chemistry, Manufacturing, and Controls (CMC) will continue to dominate the ANDA submission, review, and approval process. Therefore, generating sound technical data, avoiding methods validation/transfer related issues, physico-chemical characterization details, process details where needed along with risk management awareness and explaining them in the submission are essential. Refuse to receive letters are issued for missing information or links, inadequate data, more than one orientation data during storage for liquid/semisolid products etc. There are also several drugs that belong to the ‘complex generics’ world, where either the API or the drug product or both are considered ‘complex’ and require multi-tiered approach to development. The ANDA submission has to make a compelling case through the use of Product and Process development reports. Enough details need to be in the ANDA applications to identify, and mitigate risks involved; produce a high-quality product batch after batch which has marketability for two years or more. Details of characterization prior to initial submission batches are made requires a well planned, and executed strategy.

Bio-study (or studies) not meeting Agency expectation

The biostudy or studies (or characterizations), and dissolution data (where applicable), submitted in ANDA have to meet Agency expectation during the initial assessment of ANDAs. Though not common, a major amendment can be issued in a complete response letter requesting new batch and study, if studies do not meet Division of Bioequivalence’s expectations.

REMS impact

REMS (Risk evaluation and mitigation strategy) is a scenario that impacts some generic applications. While FDA determines REMS is necessary for certain drugs, if the Reference listed drug has REMS in place, the generics are required to have one. REMS is developed and administered by manufacturers. It covers specific requirements to educate and monitor patients to mitigate toxicity or other risks while taking medications. REMS generally result in a program which may include counseling, education, monitoring baseline and/or on-going therapy. As more generic drugs covered by REMS are submitted, ANDA applicants have to implement follow-on programs for monitoring patients.

As you prepare your ANDA for submission, it may be beneficial to enlist an outside regulatory expert to review your packet for any outstanding or conflicting information as well as ensure data accuracy prior to FDA review. Consultants such as those at EAS, with successful histories of FDA submissions, can offer fresh eyes and perspectives to strengthen your application. Whether your company chooses to move forward with your own regulatory department or outsource to another, ensure that these five critical areas are addressed for swifter reviews and approvals. Contact Bryan Coleman, Senior Director for Pharmaceuticals and Medical Devices for more information.

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