Simplified Roadmap for ANDA/NDA Submission and Approval will change Pharma Landscape

FDA’s New Drug Application (NDA) and Abbreviated New Drug Application (ANDA) approval paths in their present form are complex cumbersome maze and from my perspective need lots of luck and flawless interpretation of FDA’s needs for a first pass perfect submission and acceptance. FDA has suggested that it is working on a plan to lower the review and approval time ⁽¹⁾for priority drugs. If FDA can reduce the time for priority drugs, it can also do the same for every other drug. Simplification is needed ^(2,3,4). Considerable effort on part of companies and FDA would also be needed. If accomplished, companies and patients could realize the following benefits. 

1.    Lower approval time will lower regulatory costs and improve affordability.

2.    With faster approval companies will be able to have additional revenues.

3.    Drugs would be available to the patients sooner than the current times.

Pressure has been and is being exerted by the general population on regulators ⁽¹⁾and legislators to reduce the approval time. For the drug safety regulators need to review the necessary information. 

Form 356H ⁽⁵⁾seems simple, but meeting every requirement one has to follow 21CFR314 ⁽⁶⁾and that is a challenge. From my perspective the current process ^(6,7)is cumbersome and complex. It seems to be fraught with what I call considerable legalese, extensive intellectual complexities and ambiguities. An average person will require lot of explanation, hand holding and simplification to complete the necessary requirements. 

I have my own perspective of how the ANDA approval process can be simplified and still meet what is required by FDA and other regulatory entities. My proposal most likely would be taken as oversimplified version but could be a starting point to revamp 21CFR 314 ^{(5, 6, 7)}. ANDA Submission ⁽⁷⁾has only 38 pages but due to included references is no different from its longer version⁽⁵⁾. 21CFR 314 ⁽⁵⁾should be reviewed and simplified every so often e.g. every five years or less to meet the changing needs of pharmaceutical landscape. It should be part of FDA’s internal “continuous improvement” process. It could be considered a living document creating a “quality by design (QbD)” product. If the suggested simplifications are pursued and ultimately adopted, the NDA/ANDA approval would be much simpler than what we have and companies would realize the above suggested benefits. 

Information submitted and the filing process might not be any different from what it is today but would be much simpler step by step process as it can be easily understood by any one who is completing the application. No special expertise might be required. 

Today’s process as stated earlier requires considerable knowledge of the maze and how to comply. Many current “what if’s, dos and don’ts” of the legal maze need to be simplified and eliminated. It is my conjecture that information needed by FDA will give companies a clear definition and total command of everything one needs to know about the drug. With 90 day or less approval time companies would have incentive to do a quality filing. In FDA’s vocabulary I would call such filings “a QbD filing”. Today’s NDA/ANDA filings are a “Quality by Analysis (aggravation) QbA” filing. This needs to change.   

In Table 1 I have attempted a simple skeletal outline which could be used by the regulators to create an extremely clear and concise road map that could be precisely followed by a company for a complete application from the start. Filing requirements for NDA and ANDA fillings process would be simplified if each had their own their road maps. Elements of the road map from regulators would clearly define what they need and the industry needs to submit for a complete submission from the start. FDA or other regulators would review the submitted information for completeness and make necessary decisions to have the submitted filing granted in 90 days or less.  

I would not be surprised that many who are associated with regulatory filings and their processes would say “filing simplification can’t be done”. Effort would be needed. Change is inevitable and a necessary reality. We have that capability especially when we can send a human to the moon and brought him back safely.   

In my efforts to figure out how simplification can be done I reviewed perspective of others ^{(9, 10)}. These are interesting and should be reviewed by FDA to create the best and the simplest process. I am sure there are other ways also. Each perspective illustrates some of the challenges. They take us through the maze and could be used for simplification. Page 15 of reference 9 has a simple flow chart (road map) that could be used as a simplified process diagram for ANDA and NDA approval. FDA personnel should be familiar with Ishikawa and other logic diagrams. Such diagrams could be used to create new or be updated to improve filing and approval process. Reference 10 articulates the path via a written document.  

Again, FDA has to clearly spell out in details what information is necessary and needed from a company so that its ANDA/NDA application can be approved in 90 days or less. Spelling out the needed information and its simplification is FDA’s job as it is the most knowledgeable authority to define what is needed for approval. Based on my reading parts of CFR314 there are just too many “what ifs, dos and don’ts.” Understanding the maze can be a challenge. An Ishikawa Diagram ⁽⁸⁾or a similar logic diagram would be of great help. 

Company can take whatever time they needed for the initial submission. Once the company submits its application and FDA receives the submitted application that day becomes DAY ONE. 

In my ANDA/NDA review and approval path design each submission from the filing date gets two paths at FDA and they run parallel as illustrated in Table 1 and it looks very simple in its format and it is.

ANDA/NDA Approval Application
Inspection Path:	Application Review Path:
Based on the submitted application it is assumed that it is complete and no additional information is needed. FDA sets up the mechanism for an inspection date for the applicant site. Time period for the inspection has to be between Day 45-60 from the date of submission. These dates could be changed or cancelled based on FDA’s Application Review Path. It is important to make companies aware of the timetable so they are prepared for the inspection. This should be spelled out in the FDA road map.  If FDA informs the company of its completed application, company has to make every arrangement for such the inspection. If company does not agree to such inspection in the time window, future NDA and ANDA applications of the company should not be accepted for a prescribed time e.g. ONE year. This stipulation assures that the companies filing for approval are legitimate companies.	FDA starts the application review. If FDA does not see any discrepancy or the missing information within the first thirty days, submitted application should be deemed complete. FDA informs the company and the inspection date details that started date ONE is firmed up.  If any of the submitted application is deficient or has missing information or an explanation/clarification is needed, FDA informs the company within the thirty days or sooner from the Day One date.  FDA has to detail what all it needs for a complete application. Company has to submit the information to FDA for completeness in the next thirty days to retain its inspection date between 60-75 days from the original submission date.  If the company cannot complete and submit the needed correction/s, application goes back in the queue and the 90 day process with no fee starts all over again.  More than one FDA rejection should be deemed as a failure and no submission for the same drug should be accepted for the next two years from this company. If the company does file for the same drug it will have to pay necessary fees again. If FDA does not send any company any feedback in the first 30 days, the submission would be considered complete. If FDA does not approve the submission after 90 days, it will have to explain in writing its reasons. If FDA does not respond in any form, the submission would be considered approved and not subject to any reexamination for some time e.g. one year. However, this does not relieve company of meeting FDA's quality standards.

                                                                        Table 1

Two parallel paths should lead to a process that will be fast and could result in 90 day or less time approval.  Again if FDA chooses Ishikawa or similar process paths my conjecture is that Form 356 and CFR314 will become clearer and simplified. Resulting impact on the pharma landscape would be beyond our imagination. 

One of the most challenging tasks for filings these documents is understanding and overcoming mountain of acronyms and clauses one has to deal with in submitting the necessary and needed information. Understanding the alphabet soup is daunting. Simplifying them would be a challenge and could be resisted by some as it could impact their business. 

Again, FDA has to start, lead and complete the simplification process as they know what all is needed for a safe product. FDA could test simplification hypothesis internally using one selected group to compile and fill the needed information simulating submission and other selected group to review and critique the submitted information for completeness and approval. It would be a simulation of the filing and a review process. How much time the two processes take would be an excellent gauge of what all is needed to create a 90-day approval process. As stated earlier filing group can take whatever time they need but the reviewing group will have to complete the approval/disapproval task in ninety days. 

I would not be surprised if FDA has already done such simulation but most likely have not publicly shared the results of the exercise. If they have not done it, that suggests that they most likely did not have a 90-day approval process in mind. Maybe it is time.  

Reference 9, is an FDA presentation, has very interesting information about the number of approved, backlog and received ANDAs. These numbers raise a question and it is “Are the global companies filing ANDAs for the same drug and using FDA approvals to market their products in countries other than the United States and overburdening developed country regulatory system?” If so, such practice has to be stopped. Another question with so many filings is “Are the US PBM’s (pharmacy benefit managers) using FDA’s approval system to weed out companies to their advantage and maximize their profits, by artificially creating competition and dumping companies that do not meet their profit criterion”. 

If the above 90-day road map can be promulgated and adopted my conjecture is that the pharma landscape will change. This is discussed in an upcoming post. 

In any manufacturing or service process of continuous simplification is a must. It should be mandatory even for every regulatory ANDA/NDA filing and approval process. Opportunities exist. Improvements will lower prices and should improve new and generic drug availability and affordability. Better affordability should also improve revenues. It would be an overall win for humanity and there is nothing wrong with that. 

Girish Malhotra, PE

EPCOT International

       1.  Testimony of Drs. Woodcock, Marks and Shuren

2.    Can the Review and Approval Process for ANDA at USFDA be Reduced from Ten Months to Three Months? Profitability through Simplicity

3.    ANDA (Abbreviated New Drug Application) / NDA (New Drug Applications) Filing Simplification: Road Maps are a Must. Profitability through Simplicity

4.    What Is Needed for a Regulatory Approval of NDA/ANDA Filings in 90 Days? Profitability through Simplicity

5.  APPLICATION TO MARKET A NEW OR ABBREVIATED NEW DRUG OR BIOLOGIC FOR HUMAN USE, Form 356H

6.    21CFR Part 314 Applications for FDA Approval to Market a New Drug, FDA

7.    ANDA Submissions – Content and Format

8.    Ishikawa Diagram

9.    Ya, Dr. Naiqi, Deputy Director, Division of Chemistry IV Office of Generic Drugs, Generic Drugs – Application and Regulatory Review, Accessed November 14, 2018 

10. Sullivan, Thomas: FDA ANDA Submissions Content and Format of Abbreviated New Drug Applications, Policy & Medicine, May 6, 2018 accessed November 10, 2018 

Innovation In Pharmaceuticals: What Would It Take & Who is Responsible?

Humans from time immemorial through their imagination, creativity and different teachings have innovated in every aspect of life and things they have done. All of this should have happened for every aspect of pharmaceutical manufacturing also. However reading FDA’s PAT guidance ⁽¹⁾ [excerpts shared below] one gets the regulatory perspective and their snap shot that suggests pharmaceutical manufacturing is trailing in innovation.

I have difficulties accepting their conjecture. We need to understand the basis and come up with a potential solution to remedy regulatory supposition. It will not be easy but we need to start a discussion. Sides will be taken and that would be healthy.

Unfortunately, the pharmaceutical industry generally has been hesitant to introduce innovative systems into the manufacturing sector for a number of reasons. One reason often cited is regulatory uncertainty, which may result from the perception that our existing regulatory system is rigid and unfavorable to the introduction of innovative systems. For example, many manufacturing procedures are treated as being frozen and many process changes are managed through regulatory submissions. In addition, other scientific and technical issues have been raised as possible reasons for this hesitancy. Nonetheless, industry's hesitancy to broadly embrace innovation in pharmaceutical manufacturing is undesirable from a public health perspective. Efficient pharmaceutical manufacturing is a critical part of an effective U.S. health care system. The health of our citizens (and animals in their care) depends on the availability of safe, effective, and affordable medicines.

Pharmaceutical manufacturing will need to employ innovation, cutting edge scientific and engineering knowledge, along with the best principles of quality management. Nonetheless, industry's hesitancy to broadly embrace innovation in pharmaceutical manufacturing is undesirable from a public health perspective. Manufacturers are encouraged to use the latest scientific advances in pharmaceutical manufacturing and technology.  

1. Multivariate tools for design, data acquisition and analysis
2. Process analyzers
3. Process control tools
4. Continuous improvement and knowledge management tools

Like medical doctors who take a Hippocratic Oath, chemists and chemical engineers a take an “invisible” oath and apply fundamentals of chemistry, chemical engineering, their imagination and creativity to best of their ability to develop, design, justify and commercialize pharmaceutical manufacturing processes that are ecofriendly and produce quality products first time and all the time. They are graduates of the same schools that have sent man on the moon and back and sent Voyager and Cassini. Thus we should not doubt their capabilities. Human instinct of continuous improvement always sets in after the processes have been successfully commercialized.

There is a latent conjecture in regulatory guidance that the chemists and chemical engineers have not done the best to create the existing processes. I have difficulty accepting regulatory perspective that pharma needs to innovate. Something is a miss some place.

Any layperson reading guidance excerpts would think that the API (Active Pharmacceutical Ingredients) and their formulation processes were designed by seat of the pants rather than by incorporating fundamentals of chemistry and chemical engineering. I hope that was never the case and is not the case even today.

Could it be that the regulations are standing in the way of continued pharmaceutical manufacturing technology improvement and innovation? PAT ⁽¹⁾ guidance has few self-confessions in this regard when it suggests, “our existing regulatory system is rigid and unfavorable to the introduction of innovative systems.” Second clue from the guidance is “many manufacturing procedures are treated as being frozen and many process changes are managed through regulatory submissions”

There are few other clues, at least to me. 

1.     Regulators don’t trust company’s continuous process improvements and innovation for the existing processes on the belief that every improvement would change the product performance and its efficacy. Thus, the process has to be re-examined for product quality and performance. This admission could be a challenge.

2.     Many times chemists and chemical engineers see potential improvements only after the process has been commercial. In-house time and effort needed to prove equivalence, even if not necessary, along with paperwork needed to assure same product performance is either too expensive, cumbersome and not worth the effort as it takes too long to get the necessary regulatory approval. 

Suggestion of use of certain tools and methods mentioned in guidance is bothersome because without the use of these the basic design of a manufacturing process cannot be started. Thus, I am not sure of the rationale of the suggestion in the guidance.

Chemists and chemical engineers have the aspiration and take pride in designing processes that produces quality product from the get go. They have done this for as far back as time can tell. Quality by repeated analysis (QbA) (aggravation) has disastrous financial impact on the whole business process. One bad move can have catastrophic domino effect. It is Economics 101. Since it is being done in pharmaceutical manufacturing, it suggests that there are extraneous constraints forcing this scenario. If the business is highly profitable all ignored.    

Innovation in pharmaceutical manufacturing can only happen when the technocrats are given the freedom to innovate. However a qualification has to be attached to process improvements and that is the product quality and performance will not deviate from the approved product. With this freedom there should be string attached and that is if the performance is different from the approved product, company has to abandon the process change and if they don’t, the production has to be shut down. Only a financial constraint will be a deterrent to unscrupulous process innovation adventures. 

Reality is that the systems in place today are not conducive to pharmaceutical innovation once the processes have been commercialized. To change a process step, change has to be submitted for every product and can face the approval ordeal. Due to limited patent life brand products may not have the patent life for the change to come alive. Generics just do the best they can but then shy away for additional innovations for approval expense and delays.

If we want to have continuous innovation in pharmaceutical manufacturing then we need to change the current system. To change the current system regulatory bodies and the industry have to tango together. There has to be mutual trust from each side. Pharmaceutical manufacturing and regulatory product quality landscape will have to be re-sculptured.

Since better than 90% of the pharmaceuticals are produced by batch process, industry has become dependent on taking a sample almost after every step and check it for quality. Quality by analysis (aggravation) has become the norm even if the sample taken meets the specs. This has essentially established a culture and a business model that is very different from other manufacturing enterprises. Unlike other industries in pharma we see low inventory turns of raw materials, finished goods and intermediates. They require storage space and lead to poor use of assets. Whole business process is inefficient and cumbersome. Brigades vs. battalions are needed. Processes that are designed to produce quality product from the get go become victim of quality by aggravation process. Current business model has basically destroyed planned simplicity that works for every efficient manufacturing operation.  

I would ask another question to all associated with pharmaceuticals and that is “have we progressed with respect to innovations or are we progressing”. Most likely the answer is “no”. Regulators are telling the industry of what and how to innovate and the type of manufacturing process to use e.g. continuous processes ⁽²⁾. These are distractions. Regulatory abstinence of making suggestions on methods and types of processes that companies should use will have a very positive impact on pharmaceutical innovation.

I am not sure of the basis why the regulators are making suggestions of types of processes companies should use. Do they hands on experience in process development, design, scale-up, commercialization, justification and management experience in the manufacturing processes for products that are marketed? It takes significant rigor to make the suggestions.

Same wonderment also applies for many trade journal authors who postulate certain types of manufacturing processes for pharma. A process on paper is a speculation and is different from a lab process and miles apart from an actual commercial process. When rubber meets the road reality sinks in. My intent here is not to knit pick but face reality.

Industry knows and plays on its landscape. They know and need to justify every investment of new process technologies and every improvement. As suggested earlier, regulatory bodies need to facilitate these innovations and investments by reducing the approval time. As suggested earlier manufacturing process suggestions made by the regulators are a distraction. Most of the process methods and technologies have been existed and are used in industries other than pharma. My conjecture is lack of financial justification in the current business model along with regulations has prevented use of such processes and innovation.

If regulators want industry to innovation then they have to have a defined road map ⁽³⁾ that companies can follow for process and quality approval. Regulators need not know the process design and operating parameters. However, companies have to document every change. There has to be a time period in which companies can expect approval of their submission. Regulators have laid out the cGMP practices that companies have to follow. In a previous blog I suggested three months for generic ANDAs ⁽⁴⁾. New brand drug manufacturing approval process of 18 months or less could be a target. Such expectations will present challenges for the regulators. There has to be a trust established and if the trust is violated shutting down of the operation has to be the only recourse. 
Regulatory bodies should layout the expectations for every new product specifications in a certain specified time and let the innovators innovate. This will help and lower drug commercialization time.

Lack of trust and re-checking the checker seems to be the problem also. Such situations develop only when the deliverables change from the defined specifications because someone dropped the ball. Trust has to be earned and cannot be taken for granted. Any deviation from expected specifications and processes as suggested earlier should have strict penalty like closure of the facility with no “ifs and buts”.

To recap it is in the best interest of the industry to innovate and it should be allowed to continuously improve their existing processes even after the regulators have approved the produced products and as long as the expected deliverable quality is not compromised. Review of improvements made after initial approval should be on faith, trust and desire. If regulators find excursions outside the strictly defined boundary conditions, such operations should be shut down. Only strict financial constraint will keep everyone on their tows.  


Process of continuous improvement/innovation ⁽⁵⁾ will make drugs affordable and improve pharma revenue and profits. I just wonder why pharmaceutical industry shies away from win-win opportunities. Inaction suggests that the current business model needs change.

Girish Malhotra, PE
EPCOT International

1.     Guidance for Industry PAT—A Frame work for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance http://academy.gmp-compliance.org/guidemgr/files/PAT-FDA-6419FNL.PDF

2.     Malhotra, Girish: Batch, Continuous or "Fake/False" Continuous Processes in Pharmaceutical Manufacturing, Profitability through Simplicity, July 20, 2017

3.     Malhotra, Girish: ANDA (Abbreviated New Drug Application) / NDA (New Drug Applications) Filing Simplification: Road Maps are a Must, Profitability through Simplicity, May 11, 2017

4.     Malhotra, Girish: Can the Review and Approval Process for ANDA at USFDA be Reduced from Ten Months to Three Months? Profitability through Simplicity, March 25, 2017

5.   Malhotra, Girish: An Alternate Look at the Pharmaceutical World and drug affordability, Prospects, Analysis and Trends in Global Pharma, CPhI Annual Industry Report 2017, page 36-41, Accessed November 28, 2017