All opinions are my own.

Monday, April 9, 2018

The Good, The Bad, The Ugly (1) Complexities of Pharmaceutical Manufacturing

Most of the pharmaceutical products irrespective of product demand are manufactured using batch processes. Continuous manufacturing of pharmaceuticals is possible. However, process viability and product demand correlation need to be microscopically examined. Lately there has been an increasing fervor among the regulators, equipment suppliers, some research institutions/universities and consulting houses that the pharmaceuticals companies should use/adopt continuous processing for the manufacture of drugs. Use of continuous processes where relevant, applicable and economically justified is not a bad idea. It is a great idea. However, it is necessary that such processes are authenticated according to the established definition2.

Some batch pharmaceutical formulation processes are being called continuous processes. I hope we are not twisting fundamentals of science and engineering, economics and common sense to claim that we are on the leading edge of innovation when in reality, we are not. I am afraid that some of the technocrats and bureaucrats may be basking in false sense of accomplishment. Considerable monies are being spent. Such situations can impede real opportunities when they come along. I hope there is economic and science-based justification for the effort and the industry is not being led along an unreal path or being given an optical illusion.  
I have shared my perspective about what is involved and what all it takes to develop, design, scale up, commercialize and manage continuous processes especially in pharmaceutical manufacturing3-16. For my own benefit I thought it would be helpful to re-review and share what I have learnt and practiced and make sure I crossed every “t” and dotted every “i”. My observations are based on my experiences and are in no way intended to criticize or challenge opinions and perspective of others who are involved in process design, development, commercialization and management of manufacturing operations. It is very possible that I might have missed some process design considerations.

Based on my experiences it takes a village (team of chemists and chemical engineers, marketing, financial analysts, supply chain professionals, quality control, maintenance and manufacturing) at a company to think about and commercialize manufacturing processes for any chemical and related industry. Some may not want to accept it, but pharmaceutical manufacturing is a subset of the fine/specialty chemical industry. Unit processes and unit operations used in the chemical industry are also used in API and Formulation processes. API are fine/specialty chemicals that have disease curing value and excipients are inert additives that along with binders create the dose that can be easily ingested. 

Like any manufacturing, pharmaceuticals have their good, bad and ugly complexities. They are not per say identified here but anyone familiar with process design, development, manufacturing and profitability would understand them. It needs to be recognized that the technologies and equipment that can significantly simplify processing and lower manufacturing costs are well developed and practiced in the chemical industry. However, I feel that in pharmaceutical manufacturing regulatory constraints slow down process simplification and innovation. 

Product demand dictates type of process used and this applies to every business. Since pharmaceuticals are for human consumption there are regulatory compliance requirements. They add additional complexities of why, what and how the manufacturing will be controlled. 

Discussion here is focused on small molecules actives and their formulations. Biopharma are not discussed. They are in their infancy. Some concepts used in the small molecule processing can be applied in biopharma processing. They have to become affordable to capitalize on values of economies of scale. To get there, they have long ways to go. Different business model may be needed. 

Pharmaceutical manufacturing has two components and each has to be treated differently. 

      API Manufacturing 

API Manufacturing:
Active pharmaceutical ingredients (API) are toxins and are needed in small quantities to cure various diseases. Due to the small quantity needed, their dispensation in pure form is difficult. The best dispensation method is to convert them in tablets or solutions. Tablets are generally the most convenient form. 

-->Table 113 is a hypothetical illustration of requirement for different APIs needed per patient at one tablet per day at variable doses. 

Dose, mg
Patients, millions
API Kilograms needed/ year @ one tablet per day per year
API Production
Preferred process Type
Number of plants
One or More
200 *
One or More

Batch or Continuous
Could be a single continuous plant but generally batch

Could be a single continuous plant but generally batch due to multiple sites
* Orphan drug
Table 113: API Manufacturing Options

Table 1 may not look of much value but is extremely important for process design, production planning and scheduling, inventory control and product management. They tell us the good, the bad and the ugly complexities of manufacturing as they have financial impact. Actually, profit and loss of the products depends on the how they are produced, commercialized and managed. 

Since one kilogram of an active ingredient theoretically produces one million of one milligram tablets, small amount of API can fulfill demand of a large patient base. Dose and population in Table 1 determine the product demand. Chemistry and economics dictate the type of process used. Batch processes are the tradition for API manufacturing. Ways to improve productivity, product quality, profits and affordability have been discussed elsewhere3-16.  

Two of the five APIs illustrated in Table 1 (let’s assume these are generics) could be produced using continuous processes. As stated earlier batch processes are generally the first choice till the market demand increases. However, under pharma’s current business model, even if the demand increases most APIs will be produced at multiple sites by batch processes. Efforts to improve or simplify existing batch processes or transition to continuous processes are shunned. Regulations do not facilitate innovation either. Existing regulations that are focused for batch processes cannot be optimally applied to continuous processes. 

We have to acknowledge that APIs are fine/specialty chemicals. Equipment and processes used are no different from non-pharmaceutical fine/specialty chemicals. Same equipment is generally used to produce different actives. Since the equipment is not dedicated to any certain API, processes are modified17 to fit the equipment. This may be the most convenient method with least investment but generally such processes are inefficient and not the lowest cost. 

APIs are toxins. Thus, thorough equipment cleaning is a must to assure that there is no cross-contamination. Due to cleaning requirements and many products being produced at the same site, asset utilization for the API batch processes is less than optimum18-20at best. Global overcapacity does not help either. Chemistry similarity can improve asset utilization. Sometimes it is overlooked. Judicious review is necessary and potentially necessitate a different business model15


Table 213 is a hypothetical illustration of number of formulation plants or parallel trains that would be needed to produce at the 200,000 tablets per hour for different drug doses.

Like Table 1 this table might not look of much value. Besides giving us API quantity needed it also gives us the amounts of excipients needed once they are finalized. Combined information gives us process design, production planning and scheduling, inventory control and product management parameters. 

Theoretically Table 2 suggests that continuous formulation plants/trains could be used to fulfill the demand. Some processes need to be continuous as economies of scale will improve profits, cater to fluctuating demands and improve affordability. Since continuous formulation operations have never been on pharma’s plate, the product requirements are generally filled by batch processes.  

Table 2 Formulation Options

As stated earlier process development, equipment sizing and command would be extremely critical. One would have to have complete control of the stoichiometry, mixing and component distribution to assure tablet uniformity. Single formulation train operating 7,140 hours per year (50 weeks x 7 days/week x 24 hours/day x 0.85: allowing 15% downtime) requires a mindset that is very different from batch operations. Such operations are very possible but my conjecture is that due to stringent regulatory, product quality demands and process development challenges companies most likely opt to stay with batch formulation processes. Actually, batch processes due to their continued sampling, analysis and cleaning between products can be more complex to manage compared a properly designed continuous process. 

Last drug dose in Table 2 needs attention. Due to number of patients it is an orphan drug. Yearly need can be produced in a short time e.g. less than 10 days at 200,000 tablets per hour rate with very little down time. Such processes per established definition2would not be called a continuous process as the equipment would sit idle till the next run. If companies or the regulators want to call such process a continuous process are they essentially changing laws of science and engineering to propose a different definition that have not been clearly stated/proposed for public scrutiny and comments. 
It is ironic that certain extremely high-volume products (NSAID) could have been re-engineered to continuous process but stayed with batch process option.  


Pharmaceutical companies like every other corporation have the goal to maximize their economic return. API manufacturing and their formulations are two distinct and different processes needed to produce a drug dose. API manufacturing are reactive processes whereas formulations in simplistic terms are blending and tableting operations. Every designed and commercialized process has to be the most economic. Economies of scale and process methodology (batch vs. continuous) change the product cost dynamics: batch costs generally being higher than the continuous process costs.

As stated earlier even with using same/similar unit processes and unit operations being used in batch and continuous processes, different thinking goes in their development, design, scale up, commercializing and management. Since the current regulations are geared for batch processes, different regulations will have to be developed and applied for continuous processes. It would be sensible if chemists and chemical engineers who have hands-on experience in development, design, commercialization and management of such processes advise FDA and other regulators in creation of the necessary regulations. Manufacturing Advisory Committee that existed once should be revived to facilitate and expedite the development of regulations that could apply to continuous process. I am not sure if FDA and similar regulators have the staff with hands-on experience.  

In batch processes, raw materials and intermediates are generally staged and tested for quality and use. Since continuous process are time independent, testing of every raw material and intermediates is not be possible and economic. Stop and go opportunity does not exist. Every unit process and unit operation has to operate as designed. Deviation from the operating conditions would mean poor product quality and significant waste and financial loss. Absolute command of process stoichiometry and operating conditions is a must.  

Due to inherent nature of batch processes, companies in every industry sample and test intermediate samples even if QbD (quality by design) methods are incorporated in the overall design. Companies do make every attempt to minimize sampling and testing. Benefits are higher profits. However, some habits die hard and companies have to be proactive and curtail these habits. 

Every chemist and chemical engineer incorporates fundamentals of science and engineering to design and commercialize the best and the most economic process. They use existing process control technologies that have been used in the chemical/fine/specialty chemical industries for more than fifty years to meter liquids, solids and manage reactive batch and continuous processes. These work extremely well. It is bit confusing when FDA asks companies to practice QbD methods when they are the very foundation of every process design.   

Since continuous processes are time independent and processes are under control, inventories should be minimum.  Intermediate inline testing in continuous process can be done to make sure that the process is operating within the designed parameters and all is going well. Excursions outside the design limits if not caught in time can result in significant quantities of off-spec product and a financial loss.  

Raw material and intermediate sampling and testing have significant impact on supply chain and production planning. Batch processes increase in-process inventories and influence cash flow. In-process testing also extends batch cycle times and negatively impact asset utilization18,19. Collectively they increase product cost. However, raw material and work-in-process inventories can be held to a minimum in continuous processes. Production rates can be managed to meet variable product demand.  

Pharmaceutical companies like any other manufacturing companies have sufficient knowledge base and experience that has been used to produce dispensable tablets. Since they have been and are being practiced I firmly believe that they can be applied to overcome every complexity of pharmaceutical manufacturing. It seems that we are bogged down in “analysis paralysis” and wrath of regulators if changes are made to the existing manufacturing processes without their approval. 

Figure 1 is a review of a formulation option from Table 2. An assumption of 95% excipient per 5% API is made. 100% yield is used. 

Dose. Milligram
Tablets per hr.
API needed Kg. /hr.
Excipient Kg. /Hr.
API+ Excipient Kg. /Hr.
Tablets needed millions per Yr. 

Figure 1

To satisfy the demand of, Figure 1, 50 million patients per year equipment and technologies to commercialize a continuous pharmaceutical formulation operation exist.  Why companies have not commercialized continuous processes for such cases is perplexing. Are the regulations in the way or are the companies afraid to test new equipment and methods to simplify manufacturing methods and processes? 

Companies can convert the bad and the ugly complexities to good by focusing on selected drugs thereby create economies of scale and capitalize on what all has been discussed above. If done, landscape will change significantly and affordability of related drugs will improve. Most likely different or new business model would be needed. Amazon, Berkshire Hathaway, JP Morgan alliance and Veteran’s Affair21, 22initiatives, if successful, could make a difference. 

Regulations add complexity to any company wanting to take advantage of economies of scale, process simplification and transitioning from batch to continuous processes. My conjecture is that no one wants to spend monies on re-approval of the products. Regulators23are making attempts to simplify approval processes but there are external and internal challenges. Companies might not want to simplify manufacturing for the simple fact that they are profitability even with inefficient processes.  

All said and done it is ironic that in the last four decades technologies have been developed and commercialized that are beyond our imagination but we have not used available technologies to simplify pharmaceutical manufacturing that would benefit better than 50% of the global population. It would be interesting if reasons and causes can be identified. I believe that through creativity and imagination most of pharma’s complexities can be simplified and overcome. 

Girish Malhotra, PE
EPCOT International

  1. The Good and the Bad and the Ugly, 1966, Accessed March 29, 2018 
  2. Continuous Production, https://en.wikipedia.org/wiki/Continuous production, Accessed July 14, 2017
  3. Malhotra, Girish: Batch or a Continuous Process: A Choice; Pharmaceutical Processing, March 2005, Pg. 16 
  4. Malhotra, Girish: Alphabet Shuffle: Moving From QbA to QbD - An Example of Continuous Processing, Pharmaceutical Processing, February 2009 pg 12-13
  5. Malhotra, Girish: Hesitation In The Drive To A Continuous Pharmaceutical Manufacturing Process: Real or Imaginary? Pharmaceutical Processing, July 2009 pg-12-15
  6. Malhotra, Girish: The Path Towards Continuous Processing, Pharmaceutical Processing, August 2010, pgs 16-20
  7. Malhotra, Girish: Is Continuous Processing in Pharma’s Future? Profitability through Simplicity, July 24, 2012
  8. Malhotra, Girish: Continuous Process in Pharmaceutical Manufacturing: Considerations, Nuances and Challenges, Contract Pharma, June 2, 2015
  9. Malhotra, Girish: My perspective for Pharmaceutical Manufacturing Technologies/Processes and Continuous Improvements, CPhI 2015,http://epcotint.com/Pharmaevolution/GirishMalhotraSeptember2015CPhIreport.pdf  
  10. Malhotra, Girish: Continuous Pharmaceutical Processes and Their Demands, Contract Pharma, pg 37-40, April 5, 2016
  11. Malhotra, Girish: Strategies for Improving Batch or Creating Continuous Active Pharmaceutical Ingredient (API) Manufacturing Processes, Profitability through Simplicity, March 20, 2017
  12. Malhotra, Girish: Reality and Un-Reality: Continuous Processing in Pharmaceutical Manufacturing, Contract Pharma, April 3, 2017
  13. Malhotra, Girish: Batch, Continuous or "Fake/False" Continuous Processes, Profitability through Simplicity, July 20, 2017, American Pharmaceutical Review, Vol. 20 Issue 6 September/October 2017 pgs. 86-91, Contract Pharma, Nov./Dec. 2017 pgs 56-58, Chemistry Today, November/December 2017, Vol. 35(6) pgs 62-65
  14. Malhotra, Girish: Chapter 4 “Simplified Process Development and Commercialization” in  Quality by Design-Putting Theory into Practice co-published by Parenteral Drug Association and DHI Publishing© February 2011
  15. Malhotra, Girish: Strategies for Improving Batch or Creating Continuous Active Pharmaceutical Ingredient (API) Manufacturing Processes, Profitability through Simplicity, February 2011, Revised March 20, 2017 
  16. Malhotra, Girish:  Chemical Process Simplification: Improving Productivity and Sustainability John Wiley & Sons, February 2011
  17. Malhotra, Girish: Square Plug In A Round Hole: Does This Scenario Exist in Pharmaceuticals? Profitability through Simplicity, August 17, 2010, Accessed March 28, 2018
  18. Keeling, David, Lösch, Martin, Schrader, Ulf: Outlook on pharma operations, McKinsey & Company, 2010 Accessed March 28, 2018
  19. Benchmarking Shows Need to Improve Uptime, Capacity Utilization, Pharmaceutical Manufacturing, September 20, 2007, Accessed March 28, 2018 
  20. Kodipyaka, R: OSD: Challenges & Improvement Opportunities, Pharma Horizon, Vol.2(1) 2018 pg 21-22 Accessed April 2, 2018
  21. Leading U.S. Health Systems Announce Plans to Develop a Not-for-Profit Generic Drug Company, www.businesswire.com, Accesses March 1, 2018
  22. 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 February 27, 2018
  23. 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 Accessed April 4, 2018

Friday, March 9, 2018

Opportunities to Lower Drug Prices and Improve Affordability: From Creation (Manufacturing) to Consumption (Patient)

Since the beginning of 2018 “doing something” to curb ever increasing drug prices has picked up steam. I call two recent announcements 1-4 to be “constructive destructionist” 5 and if successful could have an everlasting impact and game changing influence on the pharma landscape. With their success we should expect additional entrants. 

Till recently, many have talked and proposed legislations but whenever rubber has met the road the tires have gone, or go flat and the blame games started. We have to accept the fact that anything being proposed by the legislators or put on the ballot box is not going to come to fruition. This is due to pharma lobby having significant influence on the electability of the legislators who want to stay in office for eternity. This combination has been deadly against the needs of the constituents who want justifiable lower drug prices. 

Recent initiatives are opportunities worth a review. Each presents a game changing opportunity to improve drug affordability, improve product quality, revenue and profits for the pharma landscape. In the United States drugs are acquired through two major systems, Veteran’s Affairs is for the veterans and rest of the country through mutually subsidized healthcare systems and that includes Medicare. Veteran’s Affairs along with selected Health Systems 1 (VAH) and Amazon, Berkshire Hathaway and JPMorgan 2-4 (ABM) are set to cause a perturbation to the existing mutually subsidized system when it comes to their employees. They could be start of a revolution against ever increasing drug prices. I am presenting my perspective and opportunities they present.  

Veteran’s Affairs:
There are about seven million participants in the Veteran’s Affair (VA) system. Some of us may not know but VA has its own methods for acquiring drugs at discounted prices 6. Its drug acquisition plan is unique and most likely is not entertained by the pharmaceutical companies because number of drugs offered are restricted and pharma and supply chain profits are lowered. However, pharma companies have acquiesced to avoid wrath of the US government and the country. Following guidelines have to be followed.  
Unlike Medicare, in which beneficiaries can choose drug plans, each with its own formulary, the VA offers no choice. Serving as the sole purchaser of drugs, the VA maintains a single national formulary that physicians must follow. The VA formulary is created through access restrictions on drugs. For drugs to be covered on the formulary, their makers must list all of their drugs on the Federal Supply Schedule (FSS) for federal purchasers at the price given to the most-favored nonfederal customer under comparable terms and conditions. Additionally, drug makers must offer the VA a price lower than a statutory federal price ceiling (FPC), which mandates a discount of at least 24 percent off the non-federal average manufacturer price (NFAMP), with a rebate if price increases exceed inflation.”
Even with VA’s restrictive purchasing program, February 2018 announcement 1 presents generic drug producers to capitalize on an opportunity to expand their markets (other Mutually Subsidized and Medicare systems) and increase profits and revenues. Since the healthcare systems are going to be directly working with the manufacturers, it is a unique opportunity for them to capitalize on values economies of scale and innovative manufacturing technologies 7, 8.

Mutually Subsidized Systems:

VAH and ABM alliances should use reverse calculations 10 to encourage manufacturing companies to innovate. Economies of scale and “what if” analysis can be used to improve manufacturing processes. Upside of the effort is going to be higher revenues, higher profits and lower drug costs. FDA and other regulators will have to be open  minded and proactive to make sure innovative manufacturing practices are adopted on a timely basis and commercialized 11, 12    

Figure 1 is a schematic of the supply chain that is applicable to patients in Medicare and mutually subsidized healthcare systems.  

Pharmacy benefit managers (PBM) 13, for simplicity I call them middlemen, facilitate distribution of drugs to most outside the VA system. Manufacturing and cost of API and their formulations are simple to understand 10, 14. However, under the current system pricing from formulations to the patients becomes murky and complex. However, the mystery is being slowly unraveled 15-19. States are also taking steps to contain rising prices 20, 21 

Figure 1

PBMs have made every attempt to make sure that the cost details are not readily available and the patients pay the highest drug prices. UnitedHealth 22 has announced a possible peak in the PBM “Black box”. However, till the beans of this initiative are counted and everything is black and white, it is too early to grasp the impact.      

It is interesting to note that PBMs block direct import of drugs by the patients from e.g. Canada and other countries but the same drugs are imported and sold at a significantly higher price in the United States. Explanation given is the safety of the drug. This also could be considered an artificial way to keep prices up by using scare tactics. Uniform global drug standards will greatly help but they would be a challenge to establish. 

From drug price information collected in India and in US 14 (with regular insurance, Medicare and NO insurance) one can easily see the reasons why PBMs have discouraged ABM Alliance 2 to take a peak in the “Black Box”. Most can conjecture that PBMs do not want anyone to negotiate and jeopardize their profits. Sood etal 16 and Grant 17 have done an excellent review of the PBM price structure. Price multiples of between 100-1500 times from manufacturing to patients 14, 16, Table 1, should be an eye opener for the negotiators in VA and ABM Alliance. As has been said earlier economies of scale and better technologies can significantly lower these multiples. 

Table 1

Drug Price Reduction Opportunities:

Using Panel B for the money flow16 illustration, it is interesting to note how a $18.00 drug gets to the patient in the current system and sells for $100.00. 

Using sound principles of economics, chemical engineering, chemistry, economies of scale and good manufacturing practices a 20% reduction in manufactured cost will translate to about $80.00 to the patient if no improvements are done to the current PBM supply chain “Black Box”. 20% or better cost reduction in the supply chain should not be considered an out of reach of possibilities. Combined cost reductions in manufacturing and supply chain would mean that a current $100.00 drug would cost about $65.00 to the patient. I am sure $35.00 cost reduction is worth the effort. 20% cost reductions in manufacturing and in the supply chain each are not out of the realm of reality. Effort would be needed. Everyone from “Creation (manufacturing) to Consumption (patient)” will benefit financially. 

Panel B is Courtesy Sood etal 16.  

Business Model Change:

Accelerated 2018 chatter is not going to let up. It seems that the pressure to make drugs affordable or lower drug prices will continuously increase. Dan Akerson, ex CEO General Motors, said it well that If you don’t attack your own business model, trust me, somebody else will. 

So far pharma companies and PBMs have stuck with their models of creating new drugs and along with PBMs selling them at the highest price participants can afford in mutually subsidized systems. Essentially no effort has been made to improve their methods to lower drug costs. In the last few years big pharma companies have relied on orphan drugs or marginally better drugs to improve their revenues and profits. These are not going to sustain major pharma companies for the long haul.

Since generic drugs, an ever-increasing need, in the United States are distributed through PBMs, in our mutually subsidized healthcare systems even they are priced highest level Table1. We have to recognize that Pharma/PBMs major customer base is dependent on affordable drugs. Pharma/PBM business model has to change. It is time.  

There is a need and it seems that PBMs and associated companies are trying to cater to the shareholders 25 rather than the patients who are the basis of their existence. With success of VAH and ABM Alliance we could see spread of drug price reductions. Pace could accelerate. As they say “cat is out of the bag” and the question is how pharma industry and PBMs are going to participate for everyone’s benefit. My conjecture is outliers will cause a change and it will happen sooner than expected.  
Girish Malhotra, PE
EPCOT International 

  1. Leading U.S. Health Systems Announce Plans to Develop a Not-for-Profit Generic Drug Company, www.businesswire.com, Accesses March 1, 2018
  2. Triple Threat: Amazon, Berkshire, JPMorgan Rattle Health-Care Firms, The Wall Street Journal, January 30, 2018, Accessed January 31, 2018
  3.  If Amazon And Buffett Lift Veil On Health Prices, Insurers Are In Trouble, Forbes.com, January 31, 2018, Accessed January 31, 2018
  4. JPMorgan to Banking Clients: Joint Health-Care Venture Is No Threat, WSJ.COM, February 4, 2018, Accessed February 4, 2018
  5.  Creative destruction: https://en.wikipedia.org/wiki/Creative destruction Accessed January 31, 2018
  6.  D’Angelo, Greg: The VA Drug Pricing Model: What Senators Should Know, The Heritage Foundation, April 11, 2007, Accessed March 5, 2018 
  7.  Malhotra, Girish:  Chemical Process Simplification: Improving Productivity and Sustainability John Wiley & Sons, February 2011
  8.  Malhotra, Girish: Innovation In Pharmaceuticals: What Would It Take & Who is Responsible?, Profitability through Simplicity, November 28, 2017, Accessed March 5, 2018
  9.  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 February 27, 2018
  10.  Malhotra, Girish: A Blueprint for Improved Pharma Competitiveness, Contract Pharma, September 8, 2014, Accessed February 28, 2018
  11. 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, Accessed March 5, 2018
  12.  Malhotra, Girish: ANDA (Abbreviated New Drug Application) / NDA (New Drug Applications) Filing Simplification: Road Maps are a Must. Profitability through Simplicity, May 11, 2017, Accessed March 5, 2018
  13.  What Is a Pharmacy Benefit Manager (PBM) And How Does A PBM Impact The Pharmacy Benefits Ecosystem?www.truveris.com, August 15, 2017, Accessed February 27, 2018
  14. Malhotra, Girish: Comparison of Drugs Prices: US vs. India; Their Manufacturing Costs & Opportunities to Improve Affordability, Profitability through Simplicity, January 18, 2018
  15.  Why Your Pharmacist Can’t Tell You That $20 Prescription Could cost Only $8, The New York Times, Accessed February 26, 2018
  16.  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
  17.  Grant, Charley, Hidden Profits In the Prescription Drug Supply Chain, The Wall Street Journal, February 26, 2018, Accessed February 27, 2018
  18.  Profits Are Hidden in the Prescription Drug Supply Chain, The Wall Street Journal, February 26, 2018, Accessed February 27, 2018
  19. Grant, Charley, White House Eyes Role of Middlemen in Drug Price Fight, The Wall Street Journal, February 12, 2018, Accessed March 1, 2018
  20.  On Drug Pricing, States Step In Where Washington Fails, The New York Times, February 27, 2018, Accessed February 27, 2018
  21.  House Bill 4005, 79Th Oregon Legislative Assembly -2018, Price and Cost of Prescription Drugs, February 26, 2018, Accessed March 5, 2018 
  22. UnitedHealth Will Pass Drug Rebates Directly to Some ConsumersThe Wall Street Journal, March 6, 2018, Accessed March 6, 2018 
  23. Private conversation with Mr. Jack Harding Jr., Harding & Harding Associates, North Canton, OH March 1, 2018
  24. Private communication with a Pharmacist at a leading pharmacy, February 26, 2018
  25. Herper, Matthew: Cigna's $54 Billion Purchase Of Express Scripts Could Upend The Prescription Drug Market, Forbes.com, March 8, 2018, Accessed March 9, 2018