Regulatory Review: Top Five Hurdles for FDA ANDA Submissions and Approvals

Radhika Rajagopalan 

The Generic Drug User Fees Amendment III (GDUFA III) program administered by the FDA Office of Generic Drugs has many promises in the making to approve quality generic drugs for the American public. The GDUFA III program, which commenced in October ’22, has improved communication with the agency to increase both ANDA approval numbers and to help complex generic drugs to enter the market. 

In addition, the FDA’s efforts at initiating Guidances, Policy and Procedure guidelines, and instructional webinars to clarify expectations for ANDAs submissions is advancing. Additionally, the ‘one cycle approval,’ a sought-after award for ANDA applicants, will be increasing. 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 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 

Controlled Correspondence is a mechanism by which agency input is obtained on many regulatory and scientific issues prior to a full-blown submission. Many ANDA applicants send the FDA-controlled correspondences prior to their 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 a real issue arises. The agency has published a guidance on this topic as well, and use of controls may negate some pitfalls. At present, under GDUFA III, controlled correspondence questions are entertained both before ANDA submission, and after a complete response letter is issued to assist the ANDA applicant. 

CMC-Related Issues 

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 in the ‘complex generics’ world, where either the API or the drug product or both are considered ‘complex’ and require a multi-tiered approach to development. The ANDA submission has to make a compelling case for their formulation and process 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 requires a well planned and executed strategy. 

Bio-Studies Not Meeting Agency Expectation 

The biostudy or studies (or characterizations), and dissolution data (where applicable), submitted in ANDA have to meet FDA expectation during the initial assessment. 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.

Patent Certifications and REMS

All ANDAs require a patent certification – Paragraph I, II, III or IV. In the case of Paragraph IV, if a new patent is listed for the RLD after an applicant submits an ANDA or information related to a patent listed for the RLD is revised after an applicant submits an ANDA, that applicant must address these changes to the patent listing for the RLD by submitting an appropriate patent certification or statement for each patent, unless the new patent information was not timely submitted to FDA by the NDA holder for the RLD. An applicant must not submit a paragraph IV certification to the ANDA for a newly listed patent “earlier than the first working day after the day the patent is published in [the Orange Book].” FDA recommends that applicants monitor the Orange Book to avoid unnecessary delays to ANDA approval. 

In addition, when ANDA applicants have failed to address new exclusivities awarded to the RLD, they may experience a delay in FDA’s approval.  

REMS (Risk evaluation and mitigation strategy) 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 that 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 help to enlist an outside regulatory expert to review your packet for any outstanding or conflicting information as well as to ensure data accuracy prior to FDA review. 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.