Can the Review and Approval Process for ANDA at USFDA be Reduced from Ten Months to Three Months?

Not having been involved with regulatory filing aspects of pharmaceuticals, reviewing Generic Drug User Fee Act Reauthorization (GDUFA II) ⁽¹⁾ was educational. After review my process simplification instincts kicked in. If the current approval time line can be reduced from TEN months to THREE months, impact of the process will be lower drug costs.

Reading joint testimony of Drs. Woodcock, Marks and Shuren ⁽²⁾ and having had time to review the application process, reinforced my thinking that a time reduction is possible but to get there industry along with USFDA would have to practice what chemical engineers and chemists are taught and asked to practice for every manufacturing process they develop, design and commercialize i.e. produce quality first time and all the time. In terms of FDA’s vocabulary the filling and review processes would have to follow QbD (Quality by Design) practices. FDA will have to follow what it has been asking the industry to practice. Industry will also have to follow suit. I believe industry will also get hands on practice about QbD and it will trickle through the whole organization, a win-win.

Many associated and proficient with regulatory filings would categorically say that filings are not a manufacturing process and such a time reduction is impossible and cannot be done. Currently filing an application is a task that is repeated by many to create quality application. It will generate higher profits for the filer if they can reduce its approval time. It can be continuously improved and deserves our attention. We improve every repetitive task to facilitate our daily lives. So why not improve the FDA ANDA (abbreviated new drug application) application filing and approval process? Improvements here could have far reaching impact for other filings also.

I firmly believe that such a time reduction is possible but many things will have to change to get there. Our thinking and work philosophy has to change. In the current application process following challenges ⁽¹⁾ have been identified. Each challenge is reviewed.

• Submission completeness: It takes about four review cycles to approve ANDA.
• Volume of applications
• Other factors. Several factors delay timely consumer access.



a) Risk Evaluation and Mitigation Strategies are used by Brand companies to delay generic entry



b) Delaying or denying generic companies’ access to reference listed drug products, thereby preventing companies from conducting studies required for approval



c) Misuse of FDA’s citizen petition process as a means to block generic approvals. 


d) FDA generally cannot approve generics until patent and exclusivity on the innovator product expire. Patent litigation and other legal challenges can frustrate timely approval. 

Submission Completeness:

In March 2, 2017 testimony Pre-ANDA program is suggested. I believe that is the most brilliant idea for filing application and reducing time. It is a step QbD implementation of the application filing process.

“About four reviews” needed for FDA application is equal to FDA using four iterations to have a quality application. Current method to get to an acceptable product (application) is a QbA (Quality by Analysis) practice. I equate QbA to “Quality by Aggravation”.

FDA also has to practice what it is suggesting companies to follow. Quoting FDA “This guidance ⁽³⁾ describes the concept that quality cannot be tested into products; (ANDA application, to me is a product of FDA’s work), in other words, it should be built-in or should be present by design.”

Yes like manufacturing processes, applications for every product are going to be different when it comes to content but the information filing requirements are essentially going to be same. I believe a template application that covers better than 90% of the filing requirements can be designed. A standard application format could pare down four reviews to a single review and completeness. This would be a monumental accomplishment. If accomplished, we will automatically see the approval time reduction.

Currently it can take up to 45 days for the FDA reviewing team to determine completeness of the application. FDA would have to figure out how this time can be reduced to 15 days. Current review practices would have to be modified. Long delays suggest that the filing team does not understand FDA’s QbD expectations or FDA has not relayed them to applicants.

FDA has to create applications that clearly state what it expects from the companies. A standard template has to be created. It's possible that the current templates do not relay FDA expectations. A redesign may be necessary. Once these applications are designed, companies and FDA staff can be trained to follow the process. Workshops could be held on a regular basis to train industry to what is needed.

I know such processes work. We had similar processes at Illinois EPA in 1972 for various industry segments. We had timelines from submission to approval of equipment design and operating permits. Based on our questions, every industry submitted relevant information that facilitated review and approval. FDA may have to benchmark to see which government agency has the best application review and approval process. Elements can be incorporated.

Another important aspect of the filing process would be to involve the engineers and chemists who have created and commercialized the process so the filled application is complete and represents a quality (QbD) filing. It means that the companies have to do their homework. They know their processes the best.

Every effort has to be made to pare ten months to 90 days. It is a doable challenge.

Volume of Applications:

FDA can go with best basis planning scenario and deal with ups and downs of the numbers. Ability to deal with such changes will be its operational finesse strategy. Many businesses deal with such scenarios. Most likely I have oversimplified the situation.

Other Factors:

*    Risk Evaluation and Mitigation Strategies are used by Brand companies to delay generic entry. 



FDA has to develop a program or strategy to prevent such harassment. Roadblock could be set but there has to be a resolution that is acceptable to each side. Generics have to be on top of their game to counter such delay tactics. Legislatorial changes might have to be incorporated. In our political system that could be a challenge.

*       Delaying or denying generic companies’ access to reference listed drug products, thereby preventing the companies from conducting studies required for approval.

Congressional intervention might be needed. USP or others who have information should be able to share the information. Congress can create a scenario to assure necessary samples are available for the generics. This would be good for their constituents. I believe FDA can intervene also.

*       Misuse of FDA’s citizen petition process as a means to block generic approvals. 



If the brand companies are abusing citizen’s petition process, there has to be a counter strategy from the generics. I have not looked at this in detail but I am sure that there are ways and means to counter this challenge.

*      FDA generally cannot approve generics until patent and exclusivity on the innovator product expire. Patent litigation and other legal challenges can frustrate timely approval. 



Generic filers have to develop their strategies. I believe if the approval time is lowered from ten months to 90 days, companies could develop workable measures. Filing company has to have a complete grasp of the situation and strategies.

If the approval process is lowered from ten months to 90 days, need for priority review most likely could disappear.

Breakdown of 90 Day Time:

I would break the 90 days in three segments. Initial review has to be completed by FDA in 15 days from acceptance of the initial application. FDA has to provide the company deficiencies of the application. Incomplete application could be rejected. Companies will have 30 days to respond FDA’s requirements. FDA would have 45 days after corrections, more than sufficient time, to review and interact with the company and act on the application.

If for some reasons the company is not able to fulfill its obligation after the initial 15 day FDA review and complete its deficiencies 30 days, they could stand to loose its application and would have to start over again. With such a possibility, it would be in the best interest of all parties to have quality application from the get go. It will be a QbD win for all.

It is very possible that facility inspections could be an encumbrance in the approval process. However, having command of the designed process would be reflected in the application. If it were not that would mean that the designed and operating process is different from the filled information. It would be tantamount to falsification of information and it should be used to ban the company from shipping products to the US market. 

What I am suggesting might be a challenge but until we take on challenges progress is never made. By posting this blog I am not questioning authority of FDA or any other government body but just presenting an alternate perspective that would bring generics to the market quicker and lower healthcare costs. I might also be incorrect in my conjectures and expectations but it would be worth if we can make an improvement and lower drug costs.

Girish Malhotra, PE

President

EPCOT International 


1.  Generic Drug User Fee Act Reauthorization (GDUFA II) Accessed March 16, 2017
2. Testimony of Drs. Woodcock, Marks and Shuren Accessed March 23, 2017
3. Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base Guidance for Industry Accessed March 24, 2017

Strategies for Improving Batch or Creating Continuous Active Pharmaceutical Ingredient (API) Manufacturing Processes

This report was originally published in March 2011.  

It is being republished and is available to any person FREE of cost via my blog Profitability through Simplicity. Please request the report using CONTACT form. 

From time to time I will be adding to this report my perspective about chemistries of various active pharmaceutical ingredients and fine/specialty chemicals that are in the public domain.

Anyone can use the information to improve their processes. Information is a guide and its use is by their own choice and will not hold anyone liable for any damage, costs or expenses. 

Scope of this research

• Enhance profitability by re-evaluating and re-engineering product development, manufacturing technologies, and commercialization methodologies.
• Evaluate ways to simplify manufacturing technologies and implement sustainable processes.
• Identify examples where process enhancements have had a substantial impact on yield and profitability.
• Understand the need for review of current patenting strategies.
• Assess the advantages of quality by design versus quality by analysis processes.

The commercialization of a new drug molecule should commence when the development of the molecule starts in the laboratory. This methodology gives the process chemist and chemical engineer familiarity with the chemicals and their properties, and allows them to share ideas and use the acquired knowledge for future projects.

An alternative business and manufacturing strategy has to be considered when catering to the drug needs of people in developing countries, who often cannot afford to pay prices of developed countries. These markets are showing 5–7% growth, compared to 2–3% in the developed countries.

Meeting regulatory needs takes precedence over having the most optimum process. In spite of companies’ efforts to meet regulations, there are often recalls due to poor practice. Recalls and citations are proof not only that the regulations are cumbersome to meet, but also that companies do not have control of their processes.

• How can my company achieve economies of scale when manufacturing APIs?
• What steps need to be taken to make it more difficult for generics companies to cannibalize market share once a drug's patent expires?
• What process manufacturing lessons can be learnt from fine/specialty chemical companies?
• Why does regulatory burden take precedence over optimizing API manufacturing processes?
• Why should chemists and chemical engineers consider the commercialization of a product whilst it is still in laboratory development?

Girish Malhotra, PE
EPCOT International

Process Simplification and The Art of Exploiting Physical Properties

Chemical additives, petrochemicals, plastics and pharmaceuticals are different reacted forms and formulations of organic (fine/specialty) and inorganic chemicals. We have mastered their use and continue to develop new uses to make our lives easier.

We are also familiar with or can find chemical and physical properties of the chemicals that are used in these applications. However, many of us have not totally understood or mastered their mutual behavior and/or how their mutual behavior can be used/manipulated/modified/exploited to simplify processes, especially the reactive processes. To some extent it is an art that can significantly improve profitability.  

Simpler processes streamline manufacturing. They are sustainable and assist in many other ways e.g. lower costs, higher profit, improve supply chain, give competitive edge through better product quality.

We have to ask ourselves a question “are we exploiting physical and chemical properties to their fullest extent?” If we are not, then the question is why not? Answer is very simple, at least to me. Values and virtues of physical and chemical are taught. However, we generally are not taught how to exploit them. I learnt from my mentors and colleagues. Shortcomings have been discussed in the past ^(1,2,3,4) and in many other publications. If we can understand and manipulate their mutual social behavior “sociochemicology” we should be able to create, design and simplify many of the reactive or formulation processes.

Collectively fault lies with us. Why? When developing a new process we don’t have the time to exploit these properties.

Opportunities are tremendous, however, getting from studying to practicing may not be the simplest. We do practice what we are taught, but not to the extent we could. Traditions also come in the way of exploitation. Most of the time textbook methods and laboratory practices are followed.

Everything has to be done yesterday and the pressure to have the process ready to be scaled up day before yesterday is omnipresent. With such constraints even the best, creative and imaginative chemists and chemical engineers can falter. Processes are commercialized and they may not be the most optimum. Generally such processes are accepted in the chemical industry. Continuous improvement opportunities allow us to better these processes. However, there are applications where commercializing a perfect process that has very stringent tolerances and meet certain regulatory needs are a must. Electronic chemicals and pharmaceuticals fit the higher tolerance regimen with pharmaceuticals due to regulations being even more demanding. Second chances in these areas can cost significant time and money.

Process Development Opportunities:

Process development is done in the laboratory and at times circumstances are not helpful to think BIG. By BIG, I mean how we will deal with commercial quantities of raw materials and intermediates. Our “Imagineering” falters somewhere when we are scaling up from the lab to a commercial process. We pay a price via higher product cost and at times with lack of first time product quality because we have not spent the time needed to create an efficient economic process.

Exploitation and imagineering of physical and chemical properties of the chemicals to create an economic process can be an art which depends on “eye of the designer”. Individual imprints come from our experiences and understanding of unit processes and unit operations.

I have used one of the physical properties as an example to illustrate how we can master/exploit sociochemicalogy to create and commercialize excellent and sustainable processes.

Liquids are Developer’s Best Friend: 

Every chemical comes in its natural state in one of the three forms: gas, solid and liquid.

At room temperature gas cannot be held in hand where as solid and liquid can be handled. When it comes to handling gases in the lab they are a challenge. Liquefied gas handling has use constraints in the lab. They can be a challenge in plants also. Special equipment would be needed if liquefied gas were to be handled. Since many labs are not equipped, gases are dissolved in a liquid and used in process development. Use of ammonia as ammonium hydroxide is an example. Process productivity can be lost when dilute gas solutions are used. Commercial handling of liquefied gases requires special attention and is product volume dependent.

In laboratory, solids are generally dissolved in appropriate solvent and used as a dissolved solution. Depending on solubility at room temperature process productivity can be significantly impacted. On commercial scale if the solid raw material can be used as a melt, it would be ideal, as the process will have high productivity. Again process economics and product demand come into play.

Raw materials, reaction intermediates and products as liquid are easiest to handle. Our ability to recognize the differences in density, mutual solubility, boiling point differences and other physical properties and exploit them to our advantage generally results in an economic and sustainable process ^(4,5,6). Exploitation of physical and chemical properties is not a cookie cutter exercise but is more like a precision surgery for each process, especially for the reactive processes.

There are many chemical reactions that can be commercially done in all liquid phase when the raw materials are solid or gas at room temperature. With sufficient residence time and using fundamental of chemistry and chemical engineering the produced product can be purified to produce global needs from a single plant. Latent advantages of such processes are very high productivity with minimal use of diluting solvents that are necessary in conventional processes. One has to imagine, explore and look. As explained earlier reason and rational for not looking in the lab is that we do not have the necessary equipment to explore such reactions. Many times such opportunities are never explored even after commercial success of such products.

Many books can be written about how sociochemicology of the chemicals can be used and improved to commercial advantage. It is best that such methods be left to the imagination of chemists and chemical engineers. Given a chance they are extremely creative, imaginative and resourceful and the results would magnificent.

Girish Malhotra, PE

EPCOT International

1. Malhotra, Girish: A Radical Approach to Fine/Specialty API Manufacturing, Profitability Through Simplicity January 20, 2010
2. Malhotra, Girish: Focus on Physical Properties To Improve Processes: Chemical Engineering, Vol. 119 No. 4 April 2012, pgs 63-66
3.  Malhotra, Girish: Industry 4.0 (Digitization): Its Benefits to Pharma and Other Chemical Industries, Profitability through Simplicity, November 11, 2016
4.  Malhotra, Girish: Chemical Process Simplification: Improving Productivity and Sustainability, ISBN: 978-0-470-48754-9, January 2011, John Wiley & Sons Inc.
5.  US patents: 3,928,457; 4,945,184; 5,004,839; 3,564,001; 4,363,914
6. McCabe, W. L. and Smith, J.C. Unit Operations of Chemical Engineering, McGraw-Hill, Inc. 1956; 40