Disclaimer

All opinions are my own.

Friday, February 23, 2024

Manufacturing Technology Innovations in Pharmaceutical Manufacturing:

 If we look at the history of disease curing products aka drugs, we will see that they started to appear about 80-90 years ago. Rapid discovery of disease curing value of existing and new disease curing chemicals and ease of their manufacture in the existing equipment being used to manufacture dyes and colorants led to an accelerated growth of the pharmaceutical industry (1). Discussion presented here is my own with the hope that any and all ambiguities I have will be clarified. Discussion is not influenced by any for profit, non-profit or regulatory body. 

 Pharmaceutical manufacturing technologies and methods: 

 

About 80-90 years ago chemical processing equipment was available and being designed for the dye and colorant industry. Many fundamentals of chemical engineering and unit operations (2,3,4,5) were explained and applied for the manufacture of various organic chemicals also called fine/specialty chemicals. They simplified manufacturing processes. Chemical engineering principles, manufacturing technologies and chemistry teachings of yester years are still the fundamental building block in every chemical manufacturing process. Active pharmaceutical ingredients (API) and their formulations are part of the same domain.  Some may disagree with this statement but one cannot change fundamentals as the methods are the same. Bio drugs are not part of the discussion. 

 

Competition and profitability has played a significant role in the development of the pharmaceutical industry. APIs, life span extenders, synthesized use same or similar equipment that was used in 1940-1960s. Except for normal enhancements/innovations with time, basic unit processes and operations have not changed. Fundamental processes and synthesis methods have not changed also. Execution methods might have changed. 

 

Fine specialty chemical companies, from (1940’s-’70s) who discovered disease curing molecules re-branded themselves as drug/pharmaceutical companies. They patented their molecules and formulations. This is very simple explanation of the landscape change. Except stricter regulatory requirements there in not much differences between fine/specialty and disease curing chemicals. Some may not agree but that is a historic reality.  

 

Due to extended time expended in discovery of disease curing molecule and regulatory approval companies have a limited patent life. To maximize profits, speed to the market is the utmost necessity. Ability and creativity of chemists and chemical engineers for use of existing equipment has been the operating mantra. Process inefficiency (low conversion) and equipment downtime (6) which can amount to as much as 50% of the available yearly equipment use time are accepted. All of these costs are passed on to the patient. 

 

Discussion here is focused on API manufacture. For formulation operating tactics, needs and philosophies are different and not part of the conversation. In the production of every product whether it is an organic additive chemical or a drug molecule annual volume of the product is important. They are based on economics and dictate manufacturing technology and methodology. No one is going to invest in any equipment and technology that is specifically designed for a product and is going to be used for a short time e.g. few weeks per year unless it is a monopoly case, patented product. Company find an alternate method/way to produce the product if any alternate equipment is/was available or modify the process to produce the product. This has been the operating philosophy in the pharma’s active ingredient (API) manufacture. As soon as the patent expires many may jump in with better manufacturing technologies. 


Still with opportunity to use better manufacturing technologies for API and their formulations innovation has stalled due to speed to market, profits and regulations. For innovation, there has to be grass root effort. Unfortunately brand companies do not have the time as their focus is speed to market and immediate profits. Generic companies have the opportunities but they have followed methods and practices of the brand companies and have not spent time to investigate/practice technologies that are better than practiced by the brand companies. My conjecture is that drug purchasing model used especially for USA drug distribution has prevented manufacturing technology innovation (7). If the generic companies could sell directly to US patient base, innovation in manufacturing technologies and methods (8) will change the landscape and shortages could be minimized and/or disappear (9)


On the API manufacturing and technology landscape few new terms have been recently introduced. I am told that they are the new technologies and simplify chemistry, process development and reduce commercialization time. These are:  


1.     Flow Chemistry

2.     Continuous manufacturing

3.     Process intensification


I do not find them anything close to new innovation but new names for well-known and practiced methods/technologies that have existed and practiced for the manufacture of chemicals for the last eighty years. I call these “fancy dance foot work” but the dance or the music has not changed. 


Flow Chemistry: I have asked for definition and clarification but have not been given a plausible answer. Folks who mention this on their curriculum vitae have not been able to explain and give definition of the term and/or an example and compare with traditional methods. Internet search suggests “Flow chemistry involves the use of channels or tubing to conduct a reaction in a continuous stream rather than a flask” (10, 11)


It is suggested that “Flow Chemistry simplifies chemistry and process development. I am not sure of this claim. I just wonder how solids would flow unless they are in liquid or solution state. Solids will have to be solubilized and that is no different from the current methods. In addition, based on the illustrated schematics it seems significant pre-engineering and investment would be need for the equipment needed. I wonder how versatile will be the applicability of the assembled equipment for different chemistries. Could they be used for other process developments? Would modifications be needed? I am not sure. 

Reviewing suggested process development methods based on use of flow chemistry (10, 11) they look to be expensive and cumbersome. This is based on the fact that information needed and used in traditional process development methods, knowledge of the physical properties of chemicals and their mutual behavior (1) would still be needed before “flow chemistry” based process contraptions described in (10, 11) can be assembled and used. A side by side economic analysis of the “flow chemistry” and traditional methods is necessary. My speculation is that the proposed methods will turn out to be financially expensive and time consuming. I hope use of term “Flow Chemistry” is not being used to impress others. 

 

Based on literature search and what I understand, incorporation of the proposed methods if possible, will be complex, expensive and time consuming. Results will be no better than what can be accomplished by current and proven methods. 

 

Based on my more than half a century of experiences in the chemical industry as a chemical engineer, generally there is methodology followed for development of chemical synthesis processes. Most of us are familiar with the methods. Reactants in appropriate solvent are added to a round bottom flask or similar equipment with its agitator and condenser and other necessary equipment. Reaction feasibility and safe operating conditions are defined. Chemist/chemical engineer generally  try different process conditions for process optimization. Next step is scale up and commercialization. 

 

Information i.e. physical, chemical properties, mutual behavior of chemicals used and produced, reaction kinetics i.e. fundamentals of chemical engineering (3, 4, 5) have to be collected by the village (1,13) and used for process development. My conjecture is that if all this is done, time needed for economic process technology development would be significantly reduced. Companies developing manufacturing technologies have to make process technology development a group activity (1,13).

 

My conjecture is that exploring what is called “flow chemistry” is an unnecessary stop i.e. prolonging process development and commercialization time. API developers/manufacturers need to think very hard on the value of proposed methods. There is an easy way to address and answer the question and it is “would the developer chemist/ chemical engineer invest their own money to develop the information that can be produced by simpler and quicker methods? 

 

We have to remember that majority of the APIs are produced using batch processes as they are fitted in the existing equipment. Information generated by “flow chemistry” methods might satisfy lab curiosity but may have minimal commercial value. Existing methods/practices can generate the same information faster. 

 

Continuous Manufacturing: In recent years “continuous processing” (14) is being touted as the way to produce APIs. No one has been able to give a satisfactory definition of “continuous processing”. When asked the definitions are confusing and they end up calling a batch process a continuous process. 

Following is my understanding of any continuous process. In every continuous chemical related process raw materials are introduced in appropriate equipment and using different unit processes and unit operations they are converted to the desired product. Each step has to be time independent. If there is fluid movement interruption, the process ceases to be a continuous process. We cannot modify established principles to suit our fancy. This also applies to drug formulations.   


Every continuous process is product specific and if another product process does not use the same unit operations, it cannot be produced year round in the same equipment. No one is going to invest in product specific equipment that is not operating year round. It is not going to have the desired financial return. 


Certain existing API products that are produced by batch process can be produced using continuous processes but for them business and operating model would have to change (1). It is my perspective that under pharma’s current sales and distribution model APIs do not have the volume to be produced continuously. An outlier producer and a different sales and distribution model (8) will be needed for continuous API production. Yes, formulations can be operated continuously but can be a challenge.  


Process intensification: This terminology is a new one for methods that have existed since the advent of chemical manufacturing and been used at least since 1960s for the manufacture of fine/specialty chemicals. If use of venturi flow, plate and frame heat exchangers, static mixers, eductors and restricted spaces to improve and enhance mixing of liquids to improve reaction chemistry is considered process intensification then this is not a new technology. It is an old art. Creativity and imagination help. Equipment economic analysis is a must.  

 

I hope we have not forgotten fundamentals of chemical engineering. Renaming existing methods that have been and are commercially used as new technologies is not ethical. Microreactors are capital intensive and have limited use. Similar results can be achieved by using existing alternate equipment.  

 

Since I am still learning, any verifiable examples are welcome. Intent here is not to challenge anyone’s knowledge or creativity but learn and augment knowledge. I have been able to use the wisdom taught by wizards of chemical engineering (3,4,5). I believe flow chemistry and process intensification are application of principles of chemical engineering that have existed and used but are worded differently to attract attention to be new. 

 

All said and done we have to remember what works in the lab does not necessarily work in the plant. Everything has to be proven before it becomes commercial. I welcome any and every meaningful discussion. API manufacturing platforms, that exist and have been continually improved, need to be judiciously considered and applied (2, 3, 4, 5). New names for the existing methods are not going to win any laurels. 

 

Judicious involvement of village (1) is needed from product inception state. This concept of technology development unlike science, is a group activity (13). Some of the processes that are the result of such village/group activity are reviewed (1). Unless there is change in how the process and technology is developed and used to commercialize better API manufacturing technologies, not much will change. Calling established processes and/or methods by new names is not new technology and is not going to reduce process development and commercialization time.

 

 

Girish Malhotra, PE

 

EPCOT International

 

1.     Malhotra, Girish: Active Pharmaceutical Manufacturing: Nondestructive Creation De Gruyter April 2022 Accessed February 17, 2024

2.     Unit Operations Accessed February 17, 2024 

3.     Unit operations of Chemical Engineering, McCabe, W.L. Smith et. al McGraw Hills Inc. 1993, Accessed February 17, 2024

4.     Walker William H. et al Principles of Chemical Engineering, McGraw Hill Book Co. Inc. 1933

5.     Levenspiel, O: Chemical Reaction Engineering, John Wiley & Sons 1999

6.     OEE Benefits for Pharmaceutical, BioTech and Medical Device Manufacturers in Life Sciences, Pharmaceutical Technology August 27, 2015

7.     Malhotra, Girish: USA’s Annual Ritual of Drug Sourcing/pricing and Shortages, Profitability through Simplicity, November 25, 2023 Accessed February 15, 2024 

8.     Malhotra, Girish: Simplified Process Development and Manufacturing of Fine/Specialty Chemicals & Active Pharmaceutical Ingredients, Profitability through Simplicity, Feb 14, 2023 

9.     Malhotra, Girish: Roadmap to Reduce Drug Shortages and Bring Pharma Manufacturing Home (US) Profitability through Simplicity, October 30, 2023 Accessed February 17, 2024

10.  Plutschack M. B. et al: The Hitchhiker’s Guide to Flow Chemistry Chemical Reviews, 2017, 11718, 11796-11893 Accessed February 17, 2024

11.  Guidi, M.  et al How to approach flow chemistry Chem. Soc. Rev.2020,498910-8932, Accessed February 17, 2024

12.  Malhotra, Girish: Chemicals tell us how to exploit their behavior for better processes. Clues are ignored. Should we? Profitability through Simplicity, June 20, 2023 Accessed February 17, 2024

13.  Kalam, APJ Abdul, Wings of Fire: An Autobiography of APJ Abdul Kalam, Sangam Books Ltd, 1999 Accessed January 31, 2024

14.  Continuous Processing   Accessed February 12, 2024

Saturday, November 25, 2023

USA’s Annual Ritual of Drug Sourcing/pricing and Shortages

In fourth quarter of every year in USA, there is a euphoria of finding the right prescription drug sourcing (1) plan. With number of players offering their plans one has to be careful to pick the right plan for their needs. It is interesting to note that we are given a filled price for the drug. Generally there is no breakdown of the components that make the payment to be made. 
 
It is generally accepted that the drugs will be available or shipped from the selected pharmacy and all will be good. It is worth noting that about 90% of the drugs dispensed are generic drugs (1, 2) and sourced through various suppliers under Medicare healthcare plans. According to US Census Bureau about 92.1 % of the US population has healthcare coverage (3). The numbers suggest that majority of the US population has access to generic drugs. However, issues of shortages and unaffordability prevails. Brand drug prices are not part of the discussion. Due to lack of any immediate competition they set their own sale prices. 
 
Pathway of the generic drug to the patient and pricing needs some explaining. PBMs (pharmacy benefit managers and their partners) purchase the drugs from manufacturers and distribute them. Their mission is maximize profits. 
 
Prescribers generally do not know the breakdown of the monies they pay i.e. cost of the drug, handling and shipping etc. Patient pays the price their drug provider charges. Table 1 reviews the price breakdown for two drugs. 
 
One of the age old trading practices is to pressure the manufacturer to lower their selling price. If the manufacturer does not make their desired profit, they will not sell the drug to PBMs and this will result in shortages. Patients will experience these. For PBMs drug becomes an “ITEM” of trade rather than a person’s life depends on it. To them profits are more important than the life of the patient/customer. 
 
Generally a cost breakdown of any drug is not in public domain. Their discussion is healthy as many ambiguities can be cleared. A cost breakdown and comparison with and without insurance (4) gives us the landscape. CostPlusdrugs.com (5) drug price breakdown is reviewed here. Prices of GoodRx.com (6) can be used for comparison. A review clears any misconception one could have. Perspective here reviews the cost of the generic drugs from the factory floor to the patient. Similar but different scale of numbers apply for the brand drugs. I am not influenced by any for or non-profit entity. Observations presented are my own. 
 
With such a large population being covered by various healthcare drug programs it is my belief that number of patients going outside their healthcare system to purchase drugs is going to be minimal. For patient going out of the network would be an anomaly. It would be same as an impulse purchase. It is  well known fact that such purchases are high priced (4). Thus listing of “retail prices” on respective sites (5,6) seems more like a scare tactic than a reality as very limited number will purchase drugs at retail prices.  

Lately drug shortages are increasing in the news. Has anyone analyzed why? Most likely no. They have a simple explanation. It is the profit at manufacturer level. Table 1 in the referred post (4) and this post clearly show the drug price component of each drug sell price. 
 
Even if manufacturing companies make a concerted effort to lower their manufacturing costs by using better processing technologies that can significantly lower their current environmental emission impact and are able to improve profits at their level, landscape will not change much. US will continue to see generic drug shortages (7) as PBMs will continue to pressure manufacturers to lower their selling prices. 
 
An analysis of adventure by Amazon, Berkshire Hathaway and J.P. Morgan (8) was bound to fail from the onset as they had no comprehensive and rational plan. Out of the box thinking” was needed but not considered (9, 10). Only viable alternate is that drug manufacturers take over the distribution and compete (7). Competition will be lower overall drug prices and will be an overall win for the country. Generally it is.  
 
Table 1 is a comparison of factory drug prices and what a customer would pay if they bought the drugs from Costplus Drug Company (5)and /or Amazon. Amazon does provide medications at discounted prices but details are not available unless one signs up (11).

It is interesting to note that the drug component even after manufacturer making 200% profit are a small percentage of the drug selling price after including handling and shipping. These charges can be as much as 700+% above the drug manufacturer’s selling price. My conjecture is that such markups apply across the generic drug sale landscape. Better API and formulation manufacturing technologies (12) and shipping and handling technology combination present an opportunity to improve profits and lower prices of drug manufacturers and their distributors.  
 
There are two notable features of Costplus Drug and GoodRx companies.  Unlike other drug plans patients do not have to become their subscriber. 




Table 1: Price comparisons

 

US healthcare system has serious issues. My conjecture is that US Legislators and policymakers have no real knowledge and/or grasp of the landscape. If they have any knowledge, it has been ignored. Drastic re-think is need. However, due to political and vested influence of many, an “ALL HANDS” re-think effort to handle the drug pricing, shortages and bring manufacturing home (7) would be needed. Patient to have the best pricing has to have knowledge of all offerings to make the best decision for themselves. This is not an easy task. Question is “Do we have what it takes to address the issues and simplify drug purchases?” or policy makers, bureaucrats will just talk about it and succumb to political pressures and do nothing?  
 
Girish Malhotra, PE
President
 
EPCOT International

 

1.   Editorial Board Bloomberg: Are Generics Too Cheap for Their Own Good? November 16, 2023
2.   https://www.fda.gov/drugs/generic-drugs/office-generic-drugs-2021-annual-report
3.   https://www.census.gov/library/publications/2023/demo/p60-281.html
4.   Malhotra, Girish: Systematic Demystification of Drug Price Mystique and the Needed Creative Destruction, Profitability through SimplicityOctober 2, 2019 
5.   Costplus Drug Company https://costplusdrugs.com
6.   GoodRx https://www.goodrx.com
7.   Malhotra, Girish: Roadmap to Reduce Drug Shortages and Bring Pharma Manufacturing Home (US), Profitability through Simplicity, October 30, 2023
8.   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
9.   Malhotra, Girish: Opportunities to Lower Drug Prices and Improve Affordability: From Creation (Manufacturing) to Consumption (Patient), Profitability through Simplicity, March 9, 2018 
10. Malhotra, Girish: Improving Drug Affordability for the United States Populous through Alternate Business Models, Profitability through Simplicity, May 4, 2018
11. Amazon: Courtesy Dr. Albinus D’Sa Senior Advisor November 19, 2023
12. Malhotra, Girish: Active Pharmaceutical Ingredient Manufacturing: Nondestructive Creation De Gruyter April 2022





Monday, October 30, 2023

Roadmap to Reduce Drug Shortages and Bring Pharma Manufacturing Home (US):

Just the thought of drawing a road map to minimize drug shortages and bring pharma manufacturing home to US has been, can be and is a daunting task in the current environment. It can give all of us shivers. US is excellent to accept any challenge that has come its way. However, it has failed miserably to minimize shortages and put forth policies to bring at least generic and essential drug manufacturing home. Our inaptitude is very evident from the fact that we have been discussing these issues for more than TEN years and done nothing. Executive Orders have been ignored (1, 2, 3). Roadblocks are our current systems and ways drugs are sold under a mutually subsidized healthcare system. 

 

I am proposing a pathway to overcome these challenges, obstacles and resolve conflicts. I am confident that improvements can be made to assure drug shortages are alleviated and pharma manufacturing comes home. My conjecture is that a totally outlandish outlier effort is needed.

 

I propose that the application filed for a generic drug be granted or denied in 90 days of filing. This is bold and very different from the current unknown time that could be anywhere between 3-4 years. Unless such steps are taken to resolve the issue of drug shortages and bringing manufacturing home, the current landscape is not going to change. Details are discussed later. 

 

Proposed plan is of significant value to pharmaceutical companies as they will have start having return on their investment compared to multiple years it takes now. This will allow companies to meet the challenge and eliminate shortages. This program could be used by the companies to invest in new manufacturing technologies and methods (4,5) to improve their profits and compete for market share as is done in any free economy. Companies will have tested their manufacturing processes and systems to start production of quality products as soon as they receive FDA approval. 

 

I have no vested interest in the outcome of the effort other than minimizing agony of fellow citizens to have food and staying healthy rather than making a choice between either (6)

 

Again, we as a country, have done nothing to eliminate drug shortages and bring their manufacturing home. Vested interests and the current participants/players including legislators have prevented anything meaningful to happen. No one wants to jeopardize their profits and vested interests. It is time we act as one country. Even with this effort profits are not going to go away. They will get just get redistributed. 

 

Food and Drug Administration (FDA), Federal Trade Commission (FTC), US Legislators and other regulatory bodies will have to spearhead, support to create systems and implement what is necessary for the 90 day plan to work. Unless these entities act together in US’s national interest with the mission to eliminate shortages and bring manufacturing home, we will continue to have legislative hearings that are meaningless (too many to cite). 

 

Across the board team effort would be needed to adopt the suggested system. Trust between the regulated and the regulators to supply approved quality drugs is critical. Any company that participates in the outlined effort should be trusted to supply FDA approved drugs. Any failure would be a cause for they not be able to supply generic drugs to the US market for the next five years. 

 

Effort made here is not perfect but is a start. I am not against profits but in the current landscape drugs are distributed through selected channels with no open competition. No one knows the real price of drugs they use is THE problem. It has to change. In US’s mutually subsidized healthcare system price truth is lost and patients suffer. My conjecture is that the current drug distribution practices are THE bottleneck and THE problem.

 

ROADMAP:

 

For success of the proposed alternate pharma companies will have to commit to participate for at least five years. If they fall short on delivering product quality and/or stop supplying drugs within the year of their approval and/or collude with any other company (manufacturing or distributor) they will be barred from supplying drugs to the US market and/or establishing a manufacturing plant in US and its territories for the next five years even if they are a current supplier to the US market. With higher than current profits and US’s open market and size companies will be continually vying for entry. This will be an excellent opportunity for generic pharma companies. Purpose of short filing and approval times is necessary as it will minimize shortage time and companies will realize faster and higher return for their investment.

 

Companies who participate in eliminating shortages and producing generic drugs in US will have to abide by extremely strict code of conduct and compete in open market. Like any other competitive business only the best will survive. They will use internal cost and profitability analysis (4) to determine their participation. Companies will compete for the customers through open market competition i.e. competitive pricing and drug efficacy. Use of innovative technologies and their application and methods (4,5) will guarantee them cost advantage. Knowledge and creativity of company personnel could be put to test. Companies will have to shed technologies that have been used for the last 60+ years (4,5). No one would like to admit this but the current manufacturing methods are mortar and pestle technologies of yester years and  need to be upgraded. It is time and challenge here might get them there.  

 

Use of drug tier (7) system, an unnecessary bureaucracy, is a needless drug segregation system. It limits competition between companies who produce FDA approved drugs. It needs to be abolished. Direct competition between companies to cure the same disease will keep the quality high and prices competitive. Again better manufacturing technologies and creativity will be a win for the patients. 

 

Generic drug producers will sell directly to the patients through mail order or similar channels thereby bypassing the existing channels that are controlled by limited distribution companies. Use of existing distribution channels is company’s choice. 

 

US’s mutually subsidized healthcare system camouflages the real drug price to patients. We have to remember that the mission of the current channels is to maximize their profits at the expense of patients. Affordability and shortages are not a consideration. 

 

Information exchange between companies and regulators:

 

Implementation of the proposed program could be a challenge for the regulators and the regulated.  For its success, current ways, methods and information required by FDA and submitted by each individual company may have to be modified. Participating companies will have processes that will deliver quality product as soon as their submission is approved in 90 days (8,9,10,11). This approval time is the KEY to the success of the proposed program. Process information and methods submitted will be used to produce the approved product.

 

90 day approval requirement is a quantum change from the current practices. USFDA might have to modify its current ways and methods for the companies to submit information about their drug manufacturing methods, their efficacy and performance. There could be significant resistance within FDA and pharmaceutical companies. However, these changes are necessary if US wants to minimize shortages and wants to bring pharmaceutical manufacturing home. We have procrastinated for too long and overlooked needs of its population and national security. 

 

For program’s success information required by FDA and/or other regulators has to be such that its personnel (chemists, chemical engineers, quality control) based on their experiences can envision every detail of the process (process, equipment, operating instruction, test methods and product quality specs etc.) without visiting the production site. FDA might have to create information templates (10, 11). These will make the basis for complete information and may allow FDA to ask for any additional information within 10 days of submission of the application. FDA will have 90 days to grant and/or deny from the date of filed application with clear explanation of every denial. Any falsified information submitted by the company will be grounds for barring the company to be in the US market for five years.  

 

FDA (Food and Drug Administration) publishes performance standard for each drug’s dispensable form. They should be available to every manufacturing entity who would like to produce and supply the drugs to the US market. 

 

It is expected that company’s staff is proficient in process development, manufacturing practices and product quality requirements from the onset. Same is expected at every filing company. Each  participating company would have to test its chemistry, process and methods so that the production of quality product is flawless. In their application they will have to include process equipment, manufacturing process, operating instructions, test methods, product specifications and other quality information etc. for their active pharmaceutical ingredient (API) manufacture and formulation methods and proof that the product meets FDA established finished performance standards. Again, information submitted by the company should be sufficient, clearly stated and would be used for every individual generic drug approval submission. Good Manufacturing Practices have to be followed.

 

It is critical that every manufacturing company provides necessary details that will allow the application reviewer adequate information so that the s/he can envision the process, the equipment and various test methods to grant and/or deny the filed application. If the information asked and provided does not provide the necessary data, it could result in denial of commercialization of the drug. An oversupply of information is always helpful.  

 

Using the filed information regulators from day of receipt will have 10 days to respond for every submitted application to the company for its completeness. If all of the information is not submitted from the onset, application most likely would be rejected in 10 days from the day of receipt. Thus, it is very critical that FDA creates near perfect information submission system that companies will use for application submission and evaluation. If complete 90 days from the filing date FDA will have to grant and/or deny their application. It will have to give definitive reasons for rejection. 

 

If the company is to produce the same drug at more than one site, it has to submit individual application and the results of the produced product from each site in their application. Any inaccurate information that will influence approval of the application will become ground for rejection and bar the company from any subsequent filing for the same drug to USA for ONE year. 

 

Compiling information can be a challenge but in the interest of customer safety and product performance, accuracy is a MUST. Perfection of information is expected as life depends on them when used. Regulators will have no hand holding meetings with companies as it is done today.  

 

To assure companies are producing and distributing drug per their approved filing FDA would randomly check the distributed finished drugs against the quality claims of each company. Independent labs can be used to test products that is being sold. Any deviation/discrepancy will be grounds for disbarment for supplying drugs to the US market for the next FIVE years. Regulators will randomly perform unannounced inspection of the facilities producing drugs being distributed in USA. Company cannot prevent unannounced inspections in their respective countries. 

 

For the outlined roadmap to succeed it is extremely critical that the information exchange between the regulator and the regulated is very accurate. This will allow each side to have an accurate understanding of the process being used to produce the desired product. There cannot be any ambiguity as inaccurate information will not allow approval of the process and significant monies will be lost. Core competencies and perfection of each team would be tested. 

 

Distribution:

 

Each pharmaceutical company that can supply approved drugs should use distribution channel of their choice to compete and sell the drugs to the directly to patients. Direct sales are the key to the success of the proposed plan. Each finished drug product manufacturer like automobiles, smart phones or laptop computers that have equivalent functioning will compete on performance and price. Current distributors can participate but cannot prevent entry of others distribution channels as long as USFDA approved products are being distributed. 

 

Since there will be no drug tier (7) system competition between drug companies for the sale of their FDA approved product/s, patient with the advice of their healthcare provider and product price can decide on the drug they want to use. 

 

Collusion:

 

If any company is found to be colluding with any other drug producer, distributor or channel to limit availability of the drug and/or increase the selling prices each would be barred from supplying drugs to the US market for the next FIVE years. FTC and each US state can investigate. Companies being investigated cannot distribute or sell any approved drug/s during the course of investigation. Companies for every frivolous investigation would be reimbursed equivalent of ONE year’s revenue for that drug. Use of ombudsman might be necessary for any conflict resolution.

 

US Production: 

 

Companies opting to produce/establish manufacturing facilities in USA using the FOUR State Model (8) should be given preference. 

It is expected that the companies who compete directly for the customers will innovate their manufacturing technologies (4) and methods and compete based on product quality. Open competition will benefit US population. My conjecture is that it will lead to manufacturing technology innovation, higher profits and higher quality products for the producing companies. This will be for US in general as it will bring new employment to the selected areas. 

 

My speculation is that what has been proposed here could be strongly objected by FDA, FTC, drug conglomerates and members of current distribution system. Legislators should back and take a lead for such proposal. I expect that in an open market, quick approval and competitive drug distribution system, drug efficacy and price would level the playing field, reduce shortages, bring pharmaceutical manufacturing home and make drugs affordable. US being the largest generic market, companies would compete on the basis of drug quality, performance and price. It will be a win for US patients and best of the generic pharmaceutical manufacturing companies. Procrastination and meaningless talk about drug shortages and bringing manufacturing home has to end. It is TIME. 

 

Girish Malhotra, PE

 

EPCOT International

 

References:

 

1.     Executive Order 13588 Reducing Prescription Drug Shortages, October 31, 2011, Accessed August 31, 2020 

2.     Executive Order 13944 https://www.govinfo.gov/content/pkg/FR-2020-08-14/pdf/2020-18012.pdf Accessed April 26, 2022

3.     Executive Order on America’s Supply Chains https://www.whitehouse.gov/briefing-room/presidential-actions/2021/02/24/executive-order-on-americas-supply-chains/ Feb. 21, 2021 Accessed May 30, 2022

4.     Malhotra, Girish: Active Pharmaceutical Ingredient Manufacturing: Nondestructive Creation Accessed February 28, 2022

  1. Malhotra, Girish: Chemical Process Simplification: Improving Productivity and Sustainability John Wiley & Sons, February 2011 

6.     Malhotra, Girish: Drug Prices: Food vs. Medicine - A Difficult Choice for Some Profitability through Simplicity June 16, 2011

7.     Understanding Drug Tiers Accessed October 22, 2023 

8.     Malhotra, Girish: ONE PAGE Road Map to Reduce Drug Shortages, Assure Quality and Improve Affordability,Profitability through Simplicity December 6, 2019

9.     Malhotra, Girish: US’s Self Sufficiency for Generic Drugs: A Supply Dilemma and Potential Solutions, Profitability through Simplicity March 31, 2022 

10.  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

11.  Malhotra, Girish: Strategies to Increase Generic Drug Competition and Bring Manufacturing to The United States of America, Profitability through Simplicity, March 16, 2020