What Is Needed for a Regulatory Approval of NDA/ANDA Filings in 90 Days?

Approving pharmaceutical manufacturing NDA/ANDA [New Drug Application/Abbreviated New Drug Application] applications at FDA in three months could be considered a Herculean task for the application filer (company) and the regulators (FDA) and it would be. But, what if, it could be done. If achievable, we would see significant changes on the pharmaceutical landscape ⁽¹⁾. Monies would be saved in dealing with regulatory affairs, would reduce the time to market. That would mean higher revenues and profits for the brand and the generic companies. It could also lead to increased competition and potentially improve drug affordability though lower costs. There would be challenges to create and incorporate such a modified filing and approval process but the benefits achieved should outweigh them.  

The existing process of NDA/ANDA filing and approval is cumbersome and a challenge for the regulated and the regulators. I have not been involved but just reviewing the documents, what is expected and needs to be done, the process is cumbersome. I have to admit that I got lost in acronyms (alphabet soup), numbers e.g. xxx (w) (a) etc. and the legal jargon. No disrespect for the creators of the jargon, this alphabet soup gave me indigestion. 

I am sure there is process to accomplish approval in ninety days. For it to happen a precise roadmap ⁽²⁾has to be created and it has to be so good that it can be followed even with eyes closed.  

Expectations from the Road Map and What would be Expected from the Regulators and the Regulated:

Putting my process development, manufacturing and management hats simultaneously I am proposing a process that would have to be developed by the regulators (FDA) and the companies for their NDA/ANDA approval. I consider filing an NDA/ANDA filing equivalent to a manufacturing process that has to be followed precisely by both sides to create a quality product ⁽³⁾, an approved NDA/ANDA filing. 

Regulators based on their years of experience will write down precise step by step recipe that has to be followed by the NDA/ANDA filing company to get their approval in the slated time. I need to emphasize that if the regulators (FDA) precisely define their expectations, the process will be smooth. There will be no doubts about the expectations in the mind of the filers. Again, information asked has to be precise and cover every detail of type of manufacturing, synthesis as well as formulation, process. It is not going to be easy and can only come from chemists, chemical engineers and other engineering disciplines who have developed, designed, commercialized and reviewed such processes and products from head to toe day in and day out.

Yes, the companies might take their own time to file, their own choice, but the expected information has to be such that there is no finger pointing suggesting “we did not know what was expected”. If companies fulfill and deliver the information as expected and every deliverable is there, company should get their approval/disapproval decision in ninety days or less. That would be a huge win for all involved. There could be some back and forth but it would be minimal and the ninety-day clock, from the day the filing was submitted, will keep ticking. i.e. no stoppage. 

I would call regulator’s road map a quality by design recipe for a perfect process created by the regulators that the filing company will follow. If for some reason the regulator’s (FDA) recipe, the defined road map, cannot be followed or understood by the company, the application process will go from Quality by Design (QbD) to Quality by Analysis, aggravation, (QbA) and that means delays and added costs.  

Once the regulators have defined their needs to approve a filing, chemists and chemical engineers at the companies have to understand the questions and deliver the answers through their submissions. Both entities will have to understand each other’s paper conversation about every process. Only their dialog will produce repeatable quality product through the asked questions and the delivered answers. If this happens, the review process will go smoothly and time reduction mission will be accomplished. 

Companies submitting information will have to have an absolute command and knowledge of their processes and will have to present information so that it will convince the regulatory examiner/s that the product is going to follow every claimed expectation and regulation that has been laid out. In short product will be of consistent and repeatable quality. If this happens I envision that the approval process in the long run will be simpler and quicker than the current process.

Examiners at the regulatory bodies will have to understand the conversed information. In some instances clarification and or additional information might be needed. My expectation is that with time such cases might be few and far in between and the expended time would be significantly less than the present process. 

What would the Showstoppers say or think? 

There will be many who will be apprehensive of the suggested process. Their perspective would be mis-information could be submitted to get fast approval. Yes that is possible but the regulators have a recourse of barring or shutting down such rouge operations. That privilege will have to be used if the current legal system stands in the way. 

I am conjecturing that for the success of this proposal regulators will draw a precise map of what they need to have from the filers. It is going to easier said than done. Regulatory staff will have to be envision and document from their past experiences what all they need for a first-time complete submission. We have to recognize that it can be done but no one is going to welcome a voluminous dissertation. 

Let’s assume that every possible information FDA or any other regulatory body asks/needs for the approval is submitted to the utmost correctness the first time and the regulator have no questions. Would the regulators accept such an application without any apprehension and approve the filing in the 90 days or sooner from the first day of filing? I am sure that there will be doubters on both sides. It will take time to accept this process as it is outside the comfort zone of filers and the regulators.  

We have to accept that will not have a perfect road map from the get go. To get to the perfect stage, I am envisioning there will be lot of obstacles from the legal and consulting firms and even the manufacturing companies. Pilot program might have to be developed by the regulators and tested and over tested. Naysayers and doubters will have their days. However, if successful pharma’s landscape will change. I believe the best minds can create a process that is much simpler than what is being followed. 

I don’t have every “t” crossed and “i” dotted for the proposed process. I may sound repeating myself at times.  Objective here is to use the proposed process to build a system that will expedite the approval process. As stated earlier results will be higher revenue for the brand and the generic companies through speedier introduction of new therapies and out of patent generics, additional competition, possibly lower drug prices and inclusion of better technologies after the products are commercial. Process of continuous improvement would be included more than ever. 

We have an opportunity to play outside the box. It could be a hip-hip hurray moment. 

Girish Malhotra. PE

EPCOT International

1.     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

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

3.     Juran, Joseph M., Juran on Quality by Design, Simon and Schuster, ISBN 9780029166833, May 1992

Past, Present and Future in Pharmaceuticals

Tea leaves about the pharmaceutical industry have been written ^(1,2), read and will continue to be written. They let us imagine, suggest us of possibilities and opportunities. We just have to decipher the maze, strive and to get there to write our own tea leaves that could be used by others to learn and innovate. It is not difficult.

Recently I was asked the following questions by American Pharmaceutical Review. Excerpts will be published and posted soon.  

1.    Looking back over the last 20 years what have been some of the most significant industry developments/trends in the following categories:

§  New classes of drugs: Some of these are improvements and others are innovations.

·      Asthma

·      Cholesterol

·      Diabetes

·      HIV/AIDS

·      HCV

·      Cancer/orphan disease cures

Drugs in each of the categories have helped and improved life. However, their affordability for the masses due to high prices is becoming increasingly limited.

§  Regulatory initiatives

FDA has issued guidelines that I believe have created more stress when it comes to manufacturing technology innovation. They have not created platform/s to simplify existing manufacturing operations and introduce better technologies. In addition, FDA has not tried to simplify filing process and reduce approval times.  

Examples are FDA’s suggestion are adoption of QbD ^(3,4)and continuous manufacturing ⁽⁵⁾for the manufacture of Active Pharmaceutical Ingredients (APIs) and their formulations. It is necessary to mention that the fundamentals of chemical engineering that have been outlined in McGraw Hill Chemical Engineering Series ⁽⁶⁾and earlier versions going to early fifties have been practiced in the manufacture of chemicals, pharmaceuticals being a subset. They detail the fundamentals that are the building block of every chemical manufacturing process, have been practiced since inception, but are being labeled as the new “coming” ^(3,4) necessary for quality products.    

Mere suggestion to incorporate QbD is indirectly telling companies that companies have short comings in their process design and don’t employ the right talent. However, one should know that without incorporation of design fundamentals repeatable quality product cannot be produced. If the companies do not build their manufacturing on this basis, they will continue to fail on cGMP practices. There will be continuing data integrity issues. In the recent years we have seen these through increasing 483 issuances ⁽⁷⁾. FDA might have to take stricter stance to curb such excursions. I just have to ask ourselves did we fail to practice what has been penned and taught by our elite educationalists. 

FDA is suggesting adoption of continuous manufacturing when it does not understand the fundamental established definition of “continuous manufacturing” that has existed and has been practiced for over 100 years. What is FDA’s definition and is it established? There is not response from FDA on this subject ⁽⁸⁾. Is FDA’s definition established by personnel who have developed, designed, commercialized and managed continuous manufacturing of APIs and formulations? It seems FDA is promoting CM as “fool’s gold”. CM can work for API (active pharmaceutical ingredients) if there is product volume demand to operate 8,760 hours per year. It is real for certain formulations that meet demand requirements outlined above. If CM’s value is not understood and applied properly, industry on the whole will end up spending billions with most likely no return. Spent monies can only be recovered via higher priced drugs. 

Continuous improvement is an ongoing exercise at every organization. FDA has been preaching it but has it practiced on its own practices. Case in point is that FDA had not done much to simplify drug or approval of manufacturing processes. A recent proposal to bring the time to eight to ten months has been suggested. Even that has issues. My question is why not complete the whole task in three months. Benefits will be tremendous i.e. lower costs and selling prices and competition. Pharma needs these. Only best of the best will survive.

§  New manufacturing technologies

     Manufacturing technology innovation comes from the companies that produce products. In the last 20 years very little of new manufacturing technologies and for that matter continuous improvements, my conjecture, has taken place on the pharma landscape that are able to lower brand and generic manufacturing costs and selling prices. I believe regulations, extended approval procedures and time are the cause. I also believe that caution within the companies, regulators will take too long to approve improvements and better technologies, are also a reason for lack of any innovation within the companies.

I believe there is more following of FDA guidances/suggestions rather than companies taking internal initiatives that will improve product quality, profitability and drug affordability. A latent reason for all this could be high profitability with existing less than efficient processes and methods.

Industry has to take the lead on manufacturing technologies. Current global pharma and that includes regulatory landscape will need significant change to get there ⁽⁹⁾.

§  Industry globalization

Hatch-Waxman Act ⁽¹⁰⁾and WTO ⁽¹¹⁾changed global pharma landscape.

When nearing patent expiration not much effort through efficient processes, which could slow down or prevent generic entry, has been made by the brand companies to retain manufacture of drugs in the developed countries. As a result most of the generic drugs are being manufactured and supplied by the India and China. Selling prices of the generics are lower compared to the brand drugs. Hatch-Waxman and WTO helped. However, the selling prices of the same generic drugs are significantly, by magnitude, lower in the developing countries compared to the developed country prices. This price differential is raising many questions about loss of intellectual property, an unfair question. Main reason for the high prices is exorbitant price hikes by the supply chain participants ^(12,13)especially in the United States to facilitate drug distribution. 

2.   Is the current state of industry what you imagined it might be 20 years ago? What do you see as some positive industry developments and what do you think the industry can do better?

     Not really. 

     Industry seems to have lost its mojo in developing breakthrough therapies for mass needs. It has produced marginally better drugs that it can sell at much higher prices to keep its revenues and profits growing. High prices have helped revenue and profit growth. With waning growth, industry has focused on cancer therapies, where it has made significant advances, and on orphan drugs. Demand especially for cancer drugs is significant. However, industry has to figure out how to make these drugs affordable. Big question is “Can the industry sustain its current business model?”

Companies selling brand drugs in the developing countries at significantly lower prices are causing consternation in the developed countries. There are too many examples to enumerate. That gives the perception in the developed countries is that the developing countries are stealing intellectual property. Reality is very different. Since the brand pharma cannot sell the drugs at the developed country prices, they sell the same drugs at significantly lower prices to recoup some of their fixed expenses. Since the major suffering population could be in the developing countries, it would be beneficial if the brand companies used  ‘economies of scale’ to sell the drugs all over at lower prices and amortized their investment over a longer period. This could be considered an alternate business model. 

My conjecture is that the develop new drugs and high price strategy has worked well and might work for few more years for about 17% of the global population. Brand pharma have catered minimally to the remaining 83% that population that also needs drugs but at affordable prices. Addressing needs of such a big population mass ⁽¹⁴⁾could give pharma companies significantly higher total revenue and profits compared to the current business model. It would require a model change. Industry may be forced to consider it if the fast pace growth of yester years stalls.

Industry and the regulators have to figure out how to reduce drug development and approval time and costs. Question we need to ask and address is that are we over analyzing the drug development and their commercial processes and as a result delaying new drug introduction at affordable costs. Industry needs to consider 7.2 billion population as the market rather than 1.2 billion. It should be obvious that the revenue from 7.2 billion would be much bigger number. Are the companies missing on simple laws of economics?

My concern for the long-term is that with the focus staying on block buster biologics and bio pharma and not many small molecule-based drugs that are affordable, the expertise to develop and commercialize such molecules is going to be lost. This could have long-term impact on job creation in the developed countries. 

3.    Looking ahead what does the industry needs to do to address growing concerns over cost, time to market, government/regulatory scrutiny, and quality/safety of products? 

Reduction in time to market is essential for the long-term viability of brand pharmaceutical companies. Regulators have to facilitate the process. This would require a major revamp in the workings of the regulators especially USFDA. Every year gain in the life of brand drug will have a significant impact on P&L statement of every company. Revamp would require a major re-do at the regulators and it would/might require a legislative interference. If they don’t, as discussed later, “creative destructors ^(15,16)” will change the current model.

Early in 2018 a new initiative to has been launched by Amazon, Berkshire Hathaway and JPMorgan ⁽¹²⁾to lower drug costs to their employees. If they are successful and they should be, it is going to be a major perturbation to make/improve drug affordability in the developed countries.

Global quality and safety of drugs is paramount. First time Issuance of 483 citation could be taken as a reflection of oversight or not crossing every “t” and dotting every “i” in their manufacturing process. However, repeated 483’s at the same company should be taken as a ground for deliberate negligence and considered for shutting the operation. Only financial hurt will prevent repeated offences.

FDA has initiated a process to reduce the approval time needed for approval to 8-10 months. However, it is still long and needs to be reduced to three months. Reduction to three months would be an incentive for the company to get to the market sooner. To achieve such a reduction in time FDA will have to create templates and facilitate applicants. There could be internal resistance within FDA and other regulators. My conjecture is companies will like this as profits are a good incentive to achieve goals.

Companies will have to comply with every FDA requirement and have to have fool proof compliance regimen. If they do not, FDA should stop manufacturing at the site. Inspection and approval time could be extended beyond three months. Reducing time to three months will be an internal challenge at FDA. 

Totally different thinking will have to implemented.

Companies have to do an internal introspection of their own practices so that they do not suffer the wrath of 483s. Every step of the manufacturing process they have to have an absolute command. One may think that this is difficult. It is difficult only if one has command of the processes. They have to think that if a manufacturer is expecting quality, they should deliver the same, no less. 

Girish Malhotra, PE

EPCOT International

1.     Malhotra, Girish: Reading the Tea Leaves: Predictions for Pharma's Future, Profitability through Simplicity, January 18, 2016 Accessed September 1, 2018

2.     Malhotra, Girish: Pharmaceutical Manufacturing Technology Innovation: Does Reading the Tea Leaves Matter? Profitability through Simplicity, December 22, 2017 Accessed September 1, 2018

3.    Hussain, Ajaz, Pharmaceutical Quality by Design: Improving Emphasis on Manufacturing Science in the 21^stCentury, Pharmaceutical Manufacturing, August 5, 2004 Accessed August 28, 2018

4.    Yu, Lawrence, Pharmaceutical Quality by Design: Product and Process Development, Understanding and Control, Pharmaceutical Research,April 2008, Volume 25, Issue 4, pp 781–791 Accessed August 26, 2018

5.     Kopcha Michael, Ph.D., R.Ph., “Continuous Manufacturing” – Common Guiding Principles Can Help Ensure Progress, September 11, 2017, FDA Voice, Accessed August 28, 2018

6.     McGraw Hill Chemical Engineering SeriesAccessed August 24, 2018

7.     Unger, Barbara: An Analysis of 2017 Warning Letters on Data Integrity, Pharmaceutical Online, May 18, 2018 Accessed August 25, 2018

8.     Drug Making Email exchange with Dr. Janet Woodcock, FDA July 13, 2016

9.     Malhotra, Girish: Pharma’s future is putting innovations in the hands of innovators, CPhI Parma Insights, August 23, 2018 Accessed August 26, 2018

10.  Hatch- Waxman Act, Very Well Health, May 31, 2018 Accessed August 29, 2018

11.  TRIPS and pharmaceutical patents, September 2006, WTO.org, Accessed August 29, 2018 

12.  Sood, N; Shih, T; Van Nuys, K; Goldman, D; The Flow of Money Through the Pharmaceutical Distribution System, June 14, 2017
 http://healthpolicy.usc.edu/Flow_of_Money_Through_the_Pharmaceutical_Distribution_System.aspx, Accessed March 1, 2018

13.  Malhotra, Girish: Opportunities to Lower Drug Prices and Improve Affordability: From Creation (Manufacturing) to Consumption (Patient), Profitability through Simplicity, March 9, 2018 Accessed August 29, 2018

14.  Malhotra, Girish: An Alternate Look at the Pharmaceutical World and Drug Affordability, CPhI Annual Industry Report 2017, pgs 36-41 

15.  Malhotra, Girish: Could Amazon (A), Berkshire Hathaway (B) and J.P. Morgan Chase (M) be the Anti Ballistic Missile (ABM) needed to Control/Curb Rising Healthcare Costs? Profitability through Simplicity, February 9, 2018 Accessed August 21, 2018

16.  Malhotra, Girish: Amazon PillPack Marriage can Alleviate Drug Shortages and May be Lower Drug Prices, Profitability through Simplicity, July 5, 2018 Accessed August 21, 2018