All opinions are my own.

Thursday, May 11, 2017

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

Excellence is expected from every task we humans do. Definition of excellence differs between humans. Due to lack of product quality consistency and excellence in pharmaceutical produced products, US FDA was created in 1906 (1). If we review the history of the US Food and Drug Administration its prime motive is to assure consistently excellent quality products (food, pharmaceuticals and cosmetics) that deliver the same performance all the time.  

Going fast forward, since I had not been involved in ANDA filings, I recently started to learn the task. I found it an extreme challenge. The process is cumbersome and even a priority approval takes time (2). I spent significant time to understand, determine and accumulate what all is needed to simplify a filing and create an ANDA application to have an approval in three months from the current expectation of ten months. FDA’s goal of approval in ten months from past practices would be a significant improvement (3, 4).  

Being a chemical engineer, I am trained to follow and communicate using a process flow diagram for the process at hand. Block process flow diagrams (5) are one of the way chemical engineers communicate information about the processes to their colleagues. Such process flow diagrams have been in use since 1840 (6).

Hoping to find a similar diagram for ANDA filings, I searched FDA websites. Yes I did find many documents that tell the readers what all is needed but I could not find a single document (showing a process flow diagram) that would tell me or anyone precisely what are the documents and information needed and their sequence. [If anyone knows existence of such road map at FDA site, please let me know.] There are lots of guidelines and guidances but during discussion with fellow professionals, I found they have different interpretation of requirements.

Simply said these documents (guidances) suggest that if five different companies were filing an ANDA for the same drug it is quite possible that none of the submissions would be exactly the same. I wonder how FDA staff will do if asked to file ANDA for a generic drug. FDA site has links that link to different documents but there are no simple flow diagrams (7). One can get lost in the maze. I would not be surprised if the number of pages in these guidances could exceed an ANDA filing application.

Since I could not find a flow chart for ANDA approval process, I thought a flow chart for New Drug Approval (NDA) (8) might exist. To my chagrin I was disappointed. Again, there were links.

The US FDA has done an excellent job in documenting and guiding what paper work is needed but I am afraid that paperwork as stated earlier can lead to personal interpretation of what all is needed and it most likely is the main cause of variations and inadequacies in filed applications and leads to delays in ANDA and NDA approvals.  

Best way to simplify the process, my perspective, would be to create/draw a road map that details each marker at every step of the way and nothing is left for interpretation. Each desired parameter has to be defined and even illustrated if need be. Simplicity is needed.

Process of filing approval for the Brand and Generic drugs is similar to any manufacturing or a service process. Every filer desires to produce a quality product (aka QbD “quality by desire”) filing. However, the current filing process can be labeled a QbA product “quality by analysis = aggravation” as it is based on individual interpretation of guidances and guidelines. I believe as stated earlier is the cause of delays and resubmissions.

I hope that once the road map for ANDA/NDA filing is created someone at USFDA will follow the road map and a file an application. Such filings should then be reviewed internally and the roadmap/ flow diagram tweaked to assure perfection. Such a process will define discrepancies and simplify the filing process. There could exceptions but in general the process will assist everyone. If done, it will lower the effort and costs related to filings. Another latent but a magnificent benefit will be that the companies will create an excellent document that is based on filers desire to create excellence. It will be a QbD (design/desire/diligence) document based on a quality by design process. I am confident that it will also assist companies to create repeatable and excellent processes that will produce quality product.

Girish Malhotra, PE
EPCOT International

  1. US FDA History Accessed May 10, 2017

  2. Malhotra, Girish: Can the Review and Approval Process for ANDA at USFDA be Reduced from Ten Months to Three Months? Accessed May 10, 2017

  3.  Generic Drug User Fee Act Reauthorization (GDUFA II) Accessed May 10, 2017

  4. Testimony of Drs. Woodcock, Marks and Shuren Accessed May 10, 2017

  5. Process Flow Diagrams Accessed May 10, 2017

  6. Cotton Processing Flowchart, Accessed May 10, 2017

  7. Abbreviated New Drug Application (ANDA): Generics Accessed May 10, 2017

  8. New Drug Application Accessed May 10, 2017

Wednesday, April 26, 2017

Would The Coating Industry’s Consolidation Lead to Manufacturing Innovation?

Change as usual is a continuous process. We have been seeing consolidation in paint and coating segment for many years. Generally consolidation leads to savings that pay for some of the monies needed for the buy out. This is normal. Savings come from better management of supply chain, information services, R&D and better manufacturing operations (1). Sherwin Williams buying Valspar and PPG Industries wooing Akzo Nobel Coatings (2) are the latest.

Significant progress has been made in the development of coatings by incorporating design of experiments and other development tools in optimizing use of various raw materials. Raw material technologies and their performance have been continuously improved. All these have led to better performance and environmentally friendly coatings.

Review of some of the consolidations suggests that one thing has not changed much and that is the manufacturing process of making coatings. Batch processes are the still norm and I call the process making one paint can at a time.

There is an explanation for paint and coatings manufacturing has not whole-heartedly ventured to continuous manufacturing. Coatings are made using batch processes with adjustments being made for raw materials and color to match the desired performance needs. This has worked from the beginning of coatings manufacture more than a century ago.

There are excellent reasons for not adopting continuous or any other manufacturing. Explanation comes from reviewing the customer’s need for different performance and colors. If we leave color aside, i.e. everything is same color “X” for the time being, one can go from low to high performance coatings by adjusting different raw material additions as the coating is being assembled in a pipeline or similar equipment. Actual task would be more challenging than as written here. Process control technologies do assist. I am sure we have sufficient creative and imaginative engineers who can deliver quality product with minimum waste during transitioning from one performance level to the next.

Moment we bring different colors to fulfill customer’s demand, industry has to stay with batch technology as development and commercialization of viable in-line color matching technology has been a challenge. Companies like Renner Herrmann (Brazil), E.I DuPont (now Axalta) and BASF initiated and progressed with the development of inline color measurement and adjustment technologies. Significant monies were spent and progress was made in the development of the technology but lack of funding and other factors led to slowdown and demise of the development at external company to commercialize the technology. It is my conjecture that since continuous manufacturing was and is alien to the coatings industry, funding and desire for such technology have been and will stay a challenge.

Continuous manufacturing, if incorporated in coatings, including automotive and industrial coatings and inks will have significant financial benefit from manufacturing technology innovation, improved inventory turns, supply chain improvements, product quality and environmental sustainability. Seasonal demands could be easily addressed.

It is my conjecture that based on the volume of coatings produced savings for the coating companies could be much higher than the general projections (1,2). As of writing of this blog it is my understanding that some companies still might be using in-line color match and adjustment technology, but who actually is using the technology is unknown. Opportunities for better manufacturing technology do exist.
  1.  Mixing it up M&A reshapes the paints and coatings industry, Chemical Week, Vol. 179, No. 10, April 3/10, 2017, Accessed April 25, 2017
  2. Akzo Nobel-PPG: Why This Trans-Atlantic Megadeal Could Actually Happen, The Wall Street Journal, March 9, 2017, Accessed April 25, 2017

Girish Malhotra, PE
EPCOT International

Saturday, March 25, 2017

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
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

Monday, March 20, 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?