Pharmaceuticals, Their Manufacturing Methods, Ecotoxicology, and Human Life Relationship

This paper was published in Pharmaceutical Processing in November 2007 [Malhotra, Girish: Pharmaceuticals, Their Manufacturing Methods, Ecotoxicology, and Human Life Relationship, Pharmaceutical Processing, November 2007 Pg 18-23]. Since the publisher is not using the site, it is being re-published in my blog as my perspective. There is no financial affiliation with any organization. 

Research on impact of pharmaceuticals on effluent is subject of continued interest.  

November 2007

A look at the impact of improper pharmaceutical waste treatment

A recent study¹ by Dr. Joakim Larsson of The Sahlgrenska Academy at Göteborg University, of the effluent water from the Patancheru wastewater treatment facility in Hyderabad, India is going to cause a global uproar about environmental regulations and pharmaceutical and chemical operations, if it has not already done so.² In and around Hyderabad, a who's who of the Indian pharmaceutical and active pharmaceutical ingredient producers and formulators have their plants. This study gives us a snapshot of the wastewater treatment plant operated by Patancheru Enviro-Tech Limited (PETL), its operating efficiency and allows us to conjecture about the state of affairs around the chemical and pharmaceutical plants. 

In his recent paper, Larsson speculates on the "impact of effluents" from active pharmaceutical plants worldwide. Every active pharmaceutical ingredient (API) and drug (combination of chemicals) are chemicals. They all have disease curing (toxic to bacteria) and life extending value. Effluent waters of API and drug manufacturing facilities have residues of these chemicals. Their levels can be toxic to the aquatic and soil life and have broad implications. 

Larsson notes that the cumulative level of 11 different APIs in the effluent water is about 36.96 milligrams per liter. These levels are a small percentage of the water outfall from the common effluent treatment plant (CETP). He suggests that the cumulative "fluoroquinolone [ciprofloxacin is a fluoroquinolone] concentration in ecotoxicological context is higher than the maximal therapeutic human plasma levels." Thus, the API concentrations at these levels have a toxicological influence on the environment, are a cause of concern, and should to be controlled. 

We need to recognize that there may be very few or no individual and/or collective ecotoxicological standards for many of the chemicals produced. Discussion of their levels and influence is outside the realm of this document. Dr. Larsson suggests that the samples from PETL contained the "highest levels of pharmaceutical ingredients in any effluent." However, there is no identification and comparison to any "other" effluents. 

Background Information (Side Bar)

1. No details about PETL are available.
2. Matrix Labs (Mylan Labs), Neuland Laboratories, and Aurobindo Pharma are fluoroquinolone producers sending their wastewater to Patancheru CETP. Along with other companies, they are shareholders of this facility.⁵ 
3. The current BOD, COD, TDS, and TSS standards Patancheru CETP has to achieve are not available. It is expected that they have to meet the standards set by APPCB. 
4. There are no ecotoxicological standards for PETL CETP and many of the APIs. 
5. There is considerable litigation about pollution due to Patancheru CETP. 

Establishing Safe Levels

 

In our efforts to curb water and soil pollution, we will have to establish individual and respective safe toxic levels of various organics and control them to below defined levels in water bodies and soil around the producing plants. Recognition of toxicity of these disease-curing chemicals presents us with two ways to reduce their levels below toxic levels:

1. Improve pharmaceutical processing and manufacturing technologies, which are considered inefficient and antiquated.³
2. Reduce organic levels in effluent water below their toxic levels. 

The initial design capacity of the PETL wastewater treatment plant is not known. However, it is expected that necessary enhancements and provisions have been made to the plant over the years to keep the operating efficiencies at the optimum level. Table 1 shows the operating results of the PETL wastewater treatment plant.

The Andhra Pradesh Pollution Control Board (APPCB) and other government bodies have to decide if the performance of the PETL operated CETP meets their set standards. From a pure numbers standpoint, it seems that there is reduction in the levels of BOD, COD, TDS, and TSS.

In addition, appropriate regulatory bodies have to decide on the toxicological impact of organics in the effluent water and the solids being sent to the landfill. Some of the background information that would be useful is not covered in the Larsson paper and is not available from APPCB⁴ (see side bar). 

Process Improvements Lead To Lower Waste

	In, mg/L	Out, mg/L
BOD (biochemical oxygen demand)	1,300	270
COD (chemical oxygen demand)	6,000	1,400
TDS (total dissolved solids)	9,000	5,000
TSS (total suspended solids)	500	300

                        

Table 1

Since all API's are a chemical and every drug is a formulation of chemicals to facilitate dispensing, implications of Dr. Larsson's work can be extended to any chemical produced anywhere. Individual organic component concentrations in the effluent point to the manufacturing efficiency of any API manufacturing facility worldwide and it needs a review. 
Based on the concentration of organics in the effluent water Patancheru CETP outfall has about 45 kilos of ciprofloxacin per day. We do not know the concentration of the ciprofloxacin coming into the treatment facility. There are two assumed scenarios:

1. Wastewater treatment facility is not able to remove any ciprofloxacin from the incoming water.
2. Wastewater treatment is removing "X%" of the ciprofloxacin from the incoming water and the rest going with the sludge.

Scenario 1: The treatment facility is not able to remove any ciprofloxacin from the water and all of it is going in the effluent water. Based on 70% yield of the manufacturing process, one can calculate that the theoretical capacity of all the plants that manufacture ciprofloxacin to be about 150 kg/day and lose about 45 kg/day in the water. At $50 per kg, the dollar loss is estimated at about $0.8 million per year at active value and about $8 million per year at the drug counter value. If the plants can improve their yield from 70 to 85%, the increased revenue for the manufacturing plants would be about $0.4 million per year. This yield improvement would also reduce the organic loading of the water leaving their respective facilities and PETL.

Scenario 2: We do not know the ciprofloxacin concentration of the incoming water or the sludge leaving the site. If the wastewater treatment facility were able to remove, for example, about 50% of the incoming ciprofloxacin in sludge and the rest goes with the effluent water, then the theoretical manufacturing capacity of the ciprofloxacin plants would be about 300 kg/day. Under these assumptions, plants loose 90 kg of ciprofloxacin per day at 70% yield. At $50.00 per kg., the API loss is estimated at about $1.6 million per year. Yield improvement of 15% would give additional revenue of about $0.8 million per year at the API level. Over the counter values are about 10 times these values. 

It is possible that many drugs and actives are pollutants in one form or other. We might be faced with a question of making a choice and balance between human needs, life extension, and environmental wellness. At some point, we humans will have to make a choice between feasible, acceptable, and affordable on each of these issues. 

Work similar to Dr. Larsson's could be done at other active pharmaceutical ingredient manufacturing, drug formulating, and chemical producing sites around the globe. It would be interesting to see the results of similar work and the potential recourse one would take to remedy the situation. 

The Patancheru study suggests that there is reduction in the value of parameters from the wastewater treatment. However, various lawsuits imply that the water and land around the facility is polluted. If the CETP operated by PETL is meeting the set standards then these lawsuits raise questions about the adequacy of the current water and soil environmental regulations for the area and around the world. If we have to meet ecotoxic standards then such standards have to be established for every chemical or their mixtures as each chemical has some ecological toxicity. This as I indicated earlier would be an arduous and expensive task. I would not venture to speculate the expense and a finish date. 

If we have to reduce the organics below the toxic level then their levels have to be established. Remediation technologies will be needed to achieve the set limits. Some existing technologies could be used and others might have to be developed. We might need to change the water pollution standard for every water body in each country. This would have to be done for soil also. Implementation of various technologies might increase the selling price of our drugs multiple times and could make them expensive. Simple-to-use measurement technologies and instrumentation to track toxic levels and can be easily used by a trained technician will have to be developed. Most likely, we do not have such methods and procedures and it could be quite an expensive and time-consuming undertaking. 

In the meantime…

While the eco-toxic data is being developed, we have another opportunity to reduce the organic levels in the effluent. Costs related to this effort are lower and there are economic benefits. We need to improve process technology and manufacturing methods of API (chemical) and drug manufacturing plants. It is the obligation of everyone associated with the pharmaceutical and chemical industry especially in process chemistry innovation, product and process development, commercialization, and manufacturing to improve the existing technologies, as they are not the best. Our pharma technologies are most inefficient and this has been echoed by USFDA and others ^6-11. Improved manufacturing technologies have dual benefit of higher profit and reduced ecological damage while serving human needs. This might look difficult and challenging but is the least expensive option and has a quick pay back. 

1. D.G. Joakim Larsson, Cecilia de Pedro, and Nicklas Paxeus, Effluent from drug manufactures contains extremely high levels of pharmaceuticals; Journal of Hazardous Materials, Volume 148, Issue 3, 30 September 2007, Pages 751-755 
2. Chemical Week: Study Finds Significant Pollution from Indian Pharma Producers, September 12, 2007 Page 39 
3. Innovation and Continuous Improvement in Pharmaceutical Manufacturing. The PAT Team and Manufacturing Science Working Group Report. http://www.fda.gov/cder/gmp/gmp2004/manufSciWP.pdf 
4. APPCB List of Industries Region Wise accessed September 14, 2007 http://www.appcb.org/list_of_industries_region_wise.html 
5. Annual Reports of Matrix Labs; 2006-2007, Neuland Laboratories, and Aurobindo Pharma: 2006-2007 accessed September 19, 2007 
6. Malhotra, Girish, Batch or a Continuous Process: A Choice; Pharmaceutical Processing, March 2005, Page 16 
7. Malhotra Girish, API Manufacture-Simplification and PAT; Pharmaceutical Processing, November 2005, Pages 24-27 
8. Malhotra, Girish, Less is More in API Process Development; Pharmaceutical Manufacturing, July/August 2005, Pages 50-51 
9. Malhotra, Girish: QBD: Myth or Reality?; Pharmaceutical Processing, February 2007, Pages 10-16 
10. Malhotra, Girish: Continuous Processes Maintain Profitability; Drug Discovery and Development, June 2007, Pages 30-31 
11. Malhotra, Girish: Big Pharma: Who's Your Role Model, Toyota or Edsel?; Pharmaceutical Manufacturing, June 2007, Page 40

Bring Pharmaceutical Manufacturing Back to USA: Additional Thoughts and Recap

This blog post recaps some of the ideas that have been proposed in the recent past and also presents some additional ideas to bring pharmaceutical manufacturing to USA. Task at hand is a challenge as many vested and personal interests that can be a major hurdle to produce active pharmaceutical ingredients (API) and their formulations in the United States of America ⁽¹⁾. Perspective presented in my own and devoid of any financial relationship with any profit or non-profit making entity. 

Recap:

Every profit making company will manufacture their products in the country where they can maximize their profits. In the last twenty five years US API producers and their formulators could not compete with imports from overseas as the US based manufacturing companies could not give the pharmacy benefit managers and insurance companies the levels of profits overseas companies could give. In addition, companies instead of innovating manufacturing technologies to deal with challenges posed by the environmental laws to preserve the eco systems opted to partner with companies that had to deal with less stringent environmental laws. These could have allowed them to capture the ever growing global markets ⁽²⁾. Consumers (patients) in the developed countries became dependent and addicted to the lower generic drug prices passed on by the companies that came from not proving bioequivalence and much less stringent environmental compliance laws. 

New considerations to bring generic pharmaceutical manufacturing: 

Ators mentioned in earlier post ⁽¹⁾ also need to consider the following if manufacture of pharma has to be brought to the United States. 

1)     Financial Incentives: Any company establishing a pharmaceutical manufacturing plant in the US should be given a TEN year tax benefit. This would be a great incentive to have a pharmaceutical (API and formulation) plant in US. Companies would lie to get this advantage.

2)     Level the playing field: Environmental Laws: Any imports of generics to US have to comply with US environmental laws at producer’s manufacturing sites ^{(3, 4, 5)}.

3)     Eliminate the Formulary lists: If a drug is approved by FDA, it means it is a useful drug for the disease, rather than being selected by PBMs (Pharmacy Benefit Manager) who are in the name of getting the best price benefiting from buying and selling.

4)     Direct Marketing to Patients: Let the pharma manufacturing companies do direct selling to patients through approved channels ^{(6, 7)}. This will bring in competition and quality, a normal expectation, through use of best technologies which has eluded pharmaceutical manufacturing. 

Recent Blog Posts:

1)     Product Quality: Any company and that includes every PBM or their agent or direct/indirect importer of generic drugs in the supply chain product quality non-conformance has to held accountable through ban of sale of such products in the US. If the product does not meet the established quality as approved by US FDA and agreed by the ANDA filing company its approval should be withdrawn ^{(1, 8, 9)}. No 483 should be issued.

2)     ANDA Approvals: Any company wanting to produce generics in US should have their ANDA review and approval done in THIRTY DAYS ^{(1, 9)}. This will be a task as US FDA will have to change its modus operandi. If FDA cannot accomplish this approval timetable and stay with the current model, there is no incentive to invest in manufacturing USA.  

It should be our expectation that our legislators and regulators (ators), who claim to be really serious about continued supply of drugs and healthcare (PPE, personal protective equipment included), will find pathways to accomplish and serve the strategic needs of the United States of America unless they are influenced by vested interests. Pharmaceutical companies will have to be proactive and compete for the market and profits. PBMs will be an interference as their profit landscape could change if direct prescription sales come to fruition. Regulators could find their influence curtailed. 

Creativity and imagination would be needed if US wants to bring pharmaceutical manufacturing home e.g. in the next 365 days. 

Girish Malhotra, PE

EPCOT International

1)     Malhotra, Girish: Euphoria to Bring Pharma Manufacturing Home to United States its Reality and Challenges, Profitability through Simplicity, May 23, 2020

2)     Malhotra, Girish: An Alternate Look at the Pharmaceutical World Revenues and Drug Affordability, Pages 2-5, CPhI Annual Industry Report, 2017

3)     Malhotra, Girish: Can Uniform Safety, Health and Effluent and Manufacturing Standards Create Process Technology Innovation and Competition in Pharmaceuticals? Profitability through Simplicity, January 10, 2017

4)     Malhotra, Girish: Why Have the Fine and Specialty Chemical Sectors Been Moving from the Developed Countries? Profitability through Simplicity, February 9, 2009

5)     Malhotra, Girish: Pharmaceuticals, Their Manufacturing Methods, Ecotoxicology, and Human Life Relationship, Pharmaceutical Processing, November 2007 

6)     Malhotra, Girish: Improving Drug Affordability for the United States Populous through Alternate Business Models, Profitability through Simplicity, May 4, 2018

7)     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

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

Euphoria to Bring Pharma Manufacturing Home to United States its Reality and Challenges

With COVID-19 amongst us suddenly every “ator” (legislator, regulator, litigator, educator, political operator, news investigator, did I miss any other) has become a policy wonk and has proposals to bring pharmaceutical manufacturing home. It is interesting that many of these “ators” have never designed, developed or seen a manufacturing plant let alone a pharmaceutical plant ^{(1,2, 3)}. Some have noble thoughts but it is not like waving a wand or twitching a nose and plant making desired active pharmaceutical ingredients (API) and their formulations will appear. Some of the “ators” at regulatory bodies ⁽⁴⁾ and educational institutions (too many to name) are even talking about advanced manufacturing technologies which they know nothing about as they have never developed, designed, commercialized such technologies at profit making enterprises. We need to be skeptical and take all of the euphoria with grain of salt and tread through the maze carefully as the task at hand is not that easy as it sounds. I am presenting my perspective and have no financial relationship with any ators or any other nonprofit and/ profit making entity. 

Since WTO (World Trade Organization) agreement US has increasingly relied on outsourced medicines. If just thinking that a manufacturing plant will appear overnight and make USA self-sufficient in pharmaceuticals then we all are living in an unreal and a make belief world. Suddenly COVID-19 brought a rude awakening home that US cannot supply its populous many of the generic drugs and faces strategic and national security threat ^{(5, 6)} and suddenly every policy wonk (ator) as stated earlier has a proposal to remedy the situation overnight. 

Unfortunately, it is not easy to accomplish task at hand overnight and even in one year. In order to accomplish success many stars have to align and many established and stodgy policies will have to change. Many are the mainstay of FDA’s day to day working. Skeptics, procrastinators, Monday morning quarterbacks, would not be needed. Mover and shakers and can doers would be extremely useful. Lots of fiefdoms and kingdoms will have to accept change. 

In order to bring pharma manufacturing home FDA would have to re-write its ANDA review and approval policies. First and foremost being it has to create processes to get ANDA approval in 30 days if a company establishes a manufacturing plant to produce quality drugs in USA ^{(7,8, 9, 10, 11)}. FDA is going to resist change as it will loose its stranglehold on pharma companies. However, it can still hold pharma companies accountable for by shutting them down if they cannot produce quality at first inspection or random sampling of their product from the market place ⁽⁶⁾. 

In addition to FDA changing its approval procedures, many other things have to happen and done by the pharma manufacturing companies. They have to create processes that can be fitted in any existing plants in the United States. It will be challenging task. Fitting a square plug in a round hole is not a simple as it sounds ^{(12, 13, 14, 15)}. Significant effort would be needed to fit the processes in existing equipment. Even with availability of plants engineers will have to figure out and prove that their process modification and innovations would deliver quality products. We don’t have time for grass root plants. 

Since pharma product is a two-step process, API manufacture and their formulations, it is an excellent opportunity to develop realcontinuous formulation operations. Equipment technologies have existed for over 60 years but my conjecture is that most equipment vendors have stood in the way of such formulation processes. This is more due to fear of engineers at pharma companies not having experience, creativity and imagination to design, develop and commercialize excellent processes that will deliver quality product ⁽¹⁶⁾. Vendors need not hold hands of clients. This not any accusation but a reality. API except for few products do not have the product volume to be produced under established continuous process definition ⁽¹⁷⁾. 

Existence of FDA is a must. It should set policies and expectations. Let the companies deliver what it expects rather than telling how and what. FDA has to let the companies innovate rather than telling them what is good for them. If the companies don’t know that then they should not be in the manufacturing business. Engineers excel in what they develop, design and commercialize. Babysitting of companies has to stop. If companies don’t live up the expected minimum after one iteration, they should not be given 483 citation but shut down. 483 have become a medal of honor ⁽¹⁸⁾ for the companies. PBMs (pharmaceutical benefit managers) will have to restrained as their profits are going to be impacted. If not restrained, US population will see drug prices go up. 

If US can send the man to the moon and bring him back, bringing pharma manufacturing home is lot easier. If companies get started to bring manufacturing to the United States today, it will take time, effort, creativity and imagination to deliver. We have to acknowledge that US does not have sustained availability of raw materials to produce the necessary drugs. There is lot needed than just saying let’s bring pharma manufacturing home. It won’t happen in a blink. US needs lot of luck. 

Girish Malhotra, PE

EPCOT International 

1. Rosebush, Lee, Outsourcing U.S. Drug Manufacturing to China was a Mistake—A Lethal One | Opinion, Newsweek, May 5, 2020, Accessed May 22, 2020
2. Gibson, Rosemary, China Rx: Exposing the Risks of America’s Dependence on China for Medicine, U.S.-China Economic and Security Review Commission, July 31, 2019, Accessed May 22, 2020
3. A Blueprint  For Enhancing the Security U.S. Pharmaceutical Supply Chain, April 2020, Accessed May 22, 2020
4. US FDA, CDER, OPQ  
5. Malhotra, Girish: Health and National Security Issues for the USA and Is The United States of America Prepared, Profitability through Simplicity, May 8, 2020 
6. Malhotra, Girish: Strategies to Increase Generic Drug Competition and Bring Manufacturing to The United States of America, Profitability through Simplicity, March 16, 2020 
7. Malhotra, Girish: Long Term Drug Quality Supplies for US, FDA and A New Reality, Profitability through Simplicity, April 3, 2020
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: Impact of Regulations, Drug Manufacturing and Pharma Supply Chain (PBMs and allies) in Drug Shortages and Affordability Part 1, Profitability through Simplicity, March 8, 2019 
10. Malhotra, Girish, Impact of Regulations, Manufacturing and Pharmaceutical Supply Chain (PBMs) on Drug Shortages and Affordability Part 2, Profitability through Simplicity, April 3, 2019
11. Malhotra, Girish: What Is Needed for a Regulatory Approval of NDA/ANDA Filings in 90 Days?, Profitability through Simplicity, October 24, 2018
12. Malhotra, Girish: Square Plug In A Round Hole: Does This Scenario Exist in Pharmaceuticals?, Profitability through Simplicity, August 17, 2010
13. Malhotra, Girish: Why Fitting a Square Plug in a Round hole is Profitable for Pharma and Most Likely Will Stay?, Profitability through Simplicity, August 1, 2014
14. Malhotra, Girish: A Radical Approach to Fine/Specialty API Manufacturing, Profitability through Simplicity, January 20, 2010
15. Malhotra, Girish: The Good, The Bad, The Ugly (1) Complexities of Pharmaceutical Manufacturing, Profitability through Simplicity, April 8, 2018
16. Vanhoorne, V, Vervaet, C: Recent progress in continuous manufacturing of oral solid dosage forms, International Journal of Pharmaceutics, April 15, 2020, Accessed May 20, 2020
17. Continuous Production,  Wikipedia
18. Malhotra, Girish: Are US FDA 483 Citations a "Medal of Honor" or “Rite of Passage” to Disgrace for the Pharma companies? Profitability through Simplicity, October 16, 2019

Health and National Security Issues for the USA and Is The United States of America Prepared

Lack of vaccine and proven treatment for COVID-19 has had the world scrambling to find treatments. Every pharma company is looking for ways to control the disease. Hydroxychloroquine and other drugs have been suggested and used. They might work on individuals but its efficacy is anecdotal. US had difficulty in acquiring sufficient dosages from overseas. FDA had to let that company it had banned to export to US ship to US. US and Indian governments at its highest levels had get involved. This brings up a point of discussion of having capabilities to acquire or produce critical drugs. There is no financial interest with any entity.

Answer to this question for the developed countries is flat NO. 

Most of the generic drugs which are better than 80% of the total US prescription market are imported from China and India ⁽¹⁾. If the drugs stop coming from these countries, US will have no capability to serve its populations pharma needs ⁽²⁾. 

I am sure US legislators are cognizant of these facts and considering alternate options. Ultimate remedy has to bring pharma manufacturing home. However, there are three bottlenecks. They are:

1. US FDA
2. Pharma lobbies
3. Pharmacy Benefit Managers (PBM)

There is no point in discussing what these have done as everyone is aware of there doings. They can implement plans to remedy the situation and bring pharma manufacturing home. 

Pharma and PBM lobbies have to be contained. In addition US FDA has to fix its broken ANDA approval system and create an environment and incentive to bring manufacturing home. Some of these plans are laid out in eth linked blogs. 

1.     What Is Needed for a Regulatory Approval of NDA/ANDA Filings in 90 Days? http://bit.ly/31ALUcu

2.     Impact of Regulations, Manufacturing and Pharmaceutical Supply Chain (PBMs) on Drug Shortages and Affordability Part 2 https://bit.ly/2TYQeOQ

3.     Drug Shortages, Quality and Prices: Who is Responsible? http://bit.ly/2oVgmAD

4.     ONE PAGE Road Map to Reduce Drug Shortages, Assure Quality and Improve Affordability http://bit.ly/34RYypH  

5.     Strategies to Increase Generic Drug Competition and Bring Manufacturing to The United States of America http://bit.ly/3d0gjaO

6.     How Would US FDA Behave/React if They Were on the Receiving End? https://bit.ly/3bwGiVW

7.     Long Term Drug Quality Supplies for US, FDA and A New Reality https://bit.ly/3aKaxZw

Above are ideas that can be used to fine-tuned to create and implement viable plans.  

Girish Malhotra, PE

EPCOT International

1. https://www.statista.com/statistics/205042/proportion-of-brand-to-generic-prescriptions-dispensed/ Accessed May 8, 2020
2. Gibson, Rosemary, China Rx: Exposing the Risks of America’s Dependence on China for Medicine, https://www.uscc.gov/sites/default/files/RosemaryGibsonTestimonyUSCCJuly152019.pdf, accessed May 8, 2020

Long Term Drug Quality Supplies for US, FDA and A New Reality

In the United States, we have come to rely on FDA to make sure that the drugs that are dispensed through pharmacies and mail order are quality drugs. However, COVID-19 has changed the immediate landscape for a while or may be forever. 

A new reality has to be accepted. We need to learn from it and plan for the long term. If we don’t, my apprehension is consequences could be grave. There in financial affiliation with any for/non profit organization. 

Since 1962 US FDA has made regulatory improvements/enhancements in assuring drug quality consistency to the US population. Generic drugs have become part of our lives. Countries have accepted US FDA standards as the gold standard. With time generic drug manufacturing has moved off-shore. FDA has made plant inspections ⁽¹⁾ part of routine NDA/ANDA approval process. Deviations from cGMP, record keeping and sanitation etc. result in 483 citation/s ⁽²⁾. However, repeats do not seem to be stern enough reprimands. They might have made companies bold, my conjecture, by taking liberties with their practices. Closure of total sites has been rare and a last resort. 

In the last SIX weeks, Charles Darwin’s “Theory of Evolution”, which occurred over millions of years has been replaced by “Reality of COVID-19 Revolution”. Globally things have changed and we are adjusting to the new reality. If we do not embrace and work with the new reality to address needs of tomorrow , people will die and we could have consequences that will be far different from what has happened to date.  

My conjecture is FDA should change certain aspects of its NDA/ANDA approval processes if it wants US population to have continued supply of quality drugs. There is an opportunity ⁽³⁾. If we don’t hold manufacturing companies are not held accountable ⁽⁴⁾, we could have prolonged ill effects due to less than quality drugs and non-availability. Their impact could be far greater than the current crisis. 

My recommendation for the US FDA is to consider an alternate proposal that was been suggested earlier ^{(3, 4)}. I am sure there are other viable proposals. My proposal can be implemented just by stork of pen and I don’t think companies, legislators or lobbyists are going to raise raucous about it as it will save lives in the short and long term. Stipulation would be that instead of having to inspect generic drug producing plants, US FDA will accept CEO/MD signature as guarantee and confirmation that the product/s being produced will meet FDA’s quality requirements and company will comply with what has been submitted in its NDA/ANDA approval application. Signature also means that if company’s product through surveillance testing do not comply with what the company says it will produce, US FDA can simply tell the company that they cannot ship their products to the United States of America for the next FOUR years. 

Consequence of above will be multifold. Companies will be spared the wrath, agony and expense of FDA inspections. They will be proactive to assure quality and use to best technologies which will force competition. FDA personnel will not have to bear the wrath of travel to remote places. They will devote more time to approve NDA/ANDA applications and will be able to create templates to simplify NDA/ANDA approval processes ⁽³⁾. 

It is understandable that with the current COVID-19 crisis, attention is focused on the immediate problem. It needs to be. However, we need to think and address how US will address continued supply of quality drugs ⁽⁴⁾ for now and future. The current crisis should be a­ lesson. If we don’t US could be holding an empty bag later part of this year or come the next crisis. 

Girish Malhotra, PE

President

EPCOT International 

1.     Inspection citations. https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-references/inspection-citation, Accessed April 3, 2020

2.     Malhotra, Girish: Are US FDA 483 Citations a "Medal of Honor" or “Rite of Passage” to Disgrace for the Pharma companies? Profitability through Simplicity, October 16, 2019

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

4.     Malhotra, Girish: ONE PAGE Road Map to Reduce Drug Shortages, Assure Quality and Improve Affordability, Profitability through Simplicity, December 6, 2010