Disclaimer

All opinions are my own.

Friday, October 5, 2018

Past, Present and Future in Pharmaceuticals


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

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

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

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

·      Asthma
·      Cholesterol
·      Diabetes
·      HIV/AIDS
·      HCV
·      Cancer/orphan disease cures

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

§  Regulatory initiatives

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

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

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

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

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

§  New manufacturing technologies

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

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

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

§  Industry globalization

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

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

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

     Not really. 

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

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

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

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

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

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

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

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

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

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

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

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


Girish Malhotra, PE
EPCOT International

1.     Malhotra, Girish: Reading the Tea Leaves: Predictions for Pharma's Future, Profitability through Simplicity, January 18, 2016 Accessed September 1, 2018
2.     Malhotra, Girish: Pharmaceutical Manufacturing Technology Innovation: Does Reading the Tea Leaves Matter? Profitability through Simplicity, December 22, 2017 Accessed September 1, 2018
3.    Hussain, Ajaz, Pharmaceutical Quality by Design: Improving Emphasis on Manufacturing Science in the 21stCentury, Pharmaceutical Manufacturing, August 5, 2004 Accessed August 28, 2018
4.    Yu, Lawrence, Pharmaceutical Quality by Design: Product and Process Development, Understanding and Control, Pharmaceutical Research,April 2008, Volume 25, Issue 4, pp 781–791 Accessed August 26, 2018
5.     Kopcha Michael, Ph.D., R.Ph., “Continuous Manufacturing” – Common Guiding Principles Can Help Ensure Progress, September 11, 2017, FDA Voice, Accessed August 28, 2018
6.     McGraw Hill Chemical Engineering SeriesAccessed August 24, 2018
7.     Unger, Barbara: An Analysis of 2017 Warning Letters on Data Integrity, Pharmaceutical Online, May 18, 2018 Accessed August 25, 2018
8.     Drug Making Email exchange with Dr. Janet Woodcock, FDA July 13, 2016
9.     Malhotra, Girish: Pharma’s future is putting innovations in the hands of innovators, CPhI Parma Insights, August 23, 2018 Accessed August 26, 2018
10.  Hatch- Waxman Act, Very Well Health, May 31, 2018 Accessed August 29, 2018
11.  TRIPS and pharmaceutical patents, September 2006, WTO.org, Accessed August 29, 2018 
12.  Sood, N; Shih, T; Van Nuys, K; Goldman, D; The Flow of Money Through the Pharmaceutical Distribution System, June 14, 2017
 
http://healthpolicy.usc.edu/Flow_of_Money_Through_the_Pharmaceutical_Distribution_System.aspx, Accessed March 1, 2018
13.  Malhotra, Girish: Opportunities to Lower Drug Prices and Improve Affordability: From Creation (Manufacturing) to Consumption (Patient), Profitability through Simplicity, March 9, 2018 Accessed August 29, 2018
14.  Malhotra, Girish: An Alternate Look at the Pharmaceutical World and Drug Affordability, CPhI Annual Industry Report 2017, pgs 36-41 
15.  Malhotra, Girish: Could Amazon (A), Berkshire Hathaway (B) and J.P. Morgan Chase (M) be the Anti Ballistic Missile (ABM) needed to Control/Curb Rising Healthcare Costs? Profitability through Simplicity, February 9, 2018 Accessed August 21, 2018
16.  Malhotra, Girish: Amazon PillPack Marriage can Alleviate Drug Shortages and May be Lower Drug Prices, Profitability through Simplicity, July 5, 2018 Accessed August 21, 2018

Thursday, July 5, 2018

Amazon PillPack Marriage can Alleviate Drug Shortages and May be Lower Drug Prices

FDA has been publishing drug shortage lists and it seems that no one is taking up the challenge to alleviate them. Reasons for the shortages have been discussed (1). I am sure there are additional. Week of June 28, 2018 a minor earthquake which could become a major disturbance to the drug pricing and supply chain happened. Amazon is buying PillPack (2). This has caused some concern on the pharma landscape. Actually Pharma companies and PBMs should be really concerned in conjunction with Amazon, Berkshire Hathaway and JP Morgan (ABM) alliance announced in January 2018 (3). I see this a tremendous opportunity for Amazon to alleviate drug shortages and improve drug affordability (4)

While the process of PillPack assimilation is going on, Amazon can directly contact the companies who can produce drugs on the shortage list directly, whet them and start supplying the drugs. This will upset the PBMs applecart. PBMs could use their political clout to threaten Amazon. However, PBMs might have to swallow a bitter pill. Amazon could extend the relationship to generic drug suppliers and lower overall drug prices. 

I believe pieces parts to alleviate drug shortages and improve drug affordability are being put in place. Pace might have to be hastened. Political entities, regulatory bodies and hospitals will be and should rooting for their success. 

Girish Malhotra, PE

EPCOT International


  1. Koons, Cynthia, Why We May Lose Generic Drugs, Bloomberg Businessweek, April 11, 2018, accessed April 18, 2018
  2.  Amazon Buys Online Pharmacy PillPack for $1 Billion, WSJ.com, Accessed July 5, 2018
  1. Triple Threat: Amazon, Berkshire, JPMorgan Rattle Health-Care Firms, The Wall Street Journal,  January 30, 2018, Accessed January 31, 2018
  2. Malhotra, Girish: Improving Drug Affordability for the United States Populous through Alternate Business Models, Profitability through Simplicity, May 4, 2108

Friday, May 4, 2018

Improving Drug Affordability for the United States Populous through Alternate Business Models

Recent layoffs and closures in the pharmaceutical industry have been on the horizon for some time. However, it seems the signs have been ignored. Blame is being put on increased pressure coming from (Pharmacy Benefit Managers) PBMs and supply chain intermediaries on drug manufacturers1 to lower their selling prices i.e. reduce profits. Simple laws of economics suggest that if companies cannot make the necessary profits under their prevailing business model, the easiest thing to do is to reduce expenses through curtailment of marginal or non-profitable businesses. Companies have to constantly tweak their business model to avert such situations. All said and done, if profits are not as expected, closures, shutdowns and layoffs are the only way to survive.

Recent articles2,3 discuss some of the details of the supply chain profits. If the numbers are correct then it seems that collectively PBMs and intermediaries may be as or more profitable than the drug manufacturers. PBMs and intermediaries by putting pressure to lower selling prices, while retaining their profits, could be leading to increasing drug shortages4 and forcing pharma company layoffs and/or closures. If the current trend continues, price controls might be one way to make drugs affordable and they would create a turmoil for PBMs and intermediaries and make their future bleak.  

Drug Distribution Models:  

In 1999, Amazon5 tried an alternate distribution model: direct selling to the patients. This disruptive model did not come to fruition. It is possible that they had not crossed every “t” and dotted every “i”. Had they succeeded drug affordability might have improved. 

Earlier in 2018 two new proposals to improve drug affordability have been suggested. They are alliance of Veterans Affairs and Intermountain Healthcare (VAH)6 and alliance of Amazon, Berkshire Hathaway and JPMorgan (ABM)7. VAH alliance will only serve veterans but parts of the proposed model can be very effectively used by ABM alliance. ABM alliance is initially intended for the employees of the three companies but my conjecture is that it could be a stepping stone for broader distribution.

The ABM Alliance selling directly to the patient population of United States will be a tremendous disruption. It would be resisted by PBMs and intermediaries. The Alliance’s success without PBMs would be like PBMs loosing their goose that laid golden eggs. My conjecture is that PBMs will make every effort to be part of this alliance. If they do not succeed, they also have their swords drawn to kill the alliance through regulatory and political/legislative pressures. They do not want to loose their cash cow. My fear is that if they are included, the ABM alliance would not fully achieve its intended goals. It is my conjecture that Amazon has learnt a lot from its 1999 attempt and would use its experience in its current attempt. 

The VAH alliance will work directly with drug manufacturers. This alliance can handle its drug distribution. Reverse calculations8 can be easily used to introduce new innovative manufacturing technologies to lower costs and maximize profits of each participant. Since they are isolated from PBMs and other intermediaries, they have an excellent possibility of success. Success here will definitely change the drug affordability landscape and sow alternate improvement ideas. Regulators will have to facilitate innovation.  

Manufacturer’s Options:

Drug manufacturers have to consider their own alternates. They need to explore them for their survival, retain their profits, minimize drug shortages and potentially avoid layoffs/closures. Continuous manufacturing improvements and technology innovation will play a significant roll. They have to be an internal company decision rather than a regulatory directive. 

Regulators need to eliminate/minimize constraints that prevent continuous improvements and innovations. 

Incorporation of economies of scale are well known method to improve manufacturer’s technologies and profits. Again, companies have to decide. As said earlier regulators have to facilitate the process. 

Gains from manufacturer’s effort can be short lived till PBMs and others catch up and force them to lower their selling prices i.e. lower profits or drive them out of business. Generic drug companies, for their survival, have to figure out how to control their destiny. They will have to recognize that economies of scale have a drawback. They can result in reduced number of facilities making the same product through better technology, thereby resulting in layoffs.

Manufacturing technology innovation for the brand drugs during the life of the patent again has to be a company decision. Brands might have to overcome regulatory obstacles as they might have to make sure that the drug efficacy and performance are not altered. Since they work under a patent time limit, they might not entertain this route.

GEN (Creative Destruction9) Alliance:

The long-term existence of the generic pharmaceutical companies depends on altering/disrupting the current model. Generic pharma companies can create their own drug distribution model (GEN Alliance) to supply drugs at affordable prices to the United States populous. This model is based on the premise that the generic drug producers want to control their survival, “profit and loss” destiny and make drugs affordable with a reliable distribution partner. It is a reconfiguration of the current model in reverse. Since it is close to the existing model it has not been explored.

I believe that lack of sales of marginally better new drugs and expensive orphan drugs are causing a dent in the profits of PBMs and intermediaries. 

To counter that they are pressuring generic drug producers and threatening their very survival. They will also make every attempt to disrupt/kill GEN Alliance through regulatory and political/legislative effort. I hope they will think about their efforts to disrupt GEN alliance as they will be going after the same generic drugs suppliers who are their current suppliers. 

Since it is reconfiguration of the existing model, many from the get go could say that it is cumbersome and unworkable. If it was easy and not disruptive, it would have been already done. It needs to be considered, reviewed, modified and exploited. We need to explore methods to make drugs affordable. Since many parts of the process exist, I believe that is  implementation should be easy.  

In the GEN Alliance some of the leading generic companies could band together and approach Amazon or Walmart or a similar entity to supply the necessary prescription drugs there by minimizing the price differentials discussed in Panel B of reference 3 and reference 4. The Alliance could be formed through their association or outside their association. Reliable distributor/s will be critical to their success. Companies will have to adhere to the prevailing laws and regulations. For this model’s success, like the ABM Alliance model, the current mutually subsidized healthcare system may have to be modified. 

I am confident that in the GEN and ABM models approved FDA drugs can be imported and significant monies can be made by selling drugs to the populous at much lower prices than the current prices. Price comparison of drugs, Table 1, in India and the United States10 shows the price differential of randomly selected drugs. Sales price in India includes manufacturers and pharmacy profits. Prices in US in Table 1 are what a patient pays with and without insurance. If all goes well drug prices could be reduced by 50% or more. Improved drug affordability could also increase sales. 

My conjecture is that through GEN alliance generic pharma companies will become masters of their destiny i.e. P&L, longevity. Competition on product quality, technology, costs and exceeding regulations will become the cornerstone. My expectation is that best of the best in each category will participate in GEN Alliance. With affordable drug prices, we all will be on a new turf.    

Nuances of VAH, ABM and GEN models:

Economies of scale, manufacturing technologies and product quality will play a significant role in all three models.
In each of these models, companies will compete on manufacturing technology and quality to gain shelf space with distributors. 

Amazon while working through its own ABM alliance could also approach the selected GEN alliance companies it sees fit to form a longterm relationship. VAH, ABM and/or GEN models if executed properly will work and would be a win-win.  

As I eluded earlier changes in the current mutually subsidized healthcare system might be needed. This task could be a challenge and in our political/economic system could be equivalent to trying to climb Mt. Everest bare feet with no oxygen. PBMs and other intermediaries will throw every barb at the participating companies. However, small successes at initial stages will make believers and hopefully generic drug prices in the United States will be realistic and out of the clutches of PBMs and intermediaries who in the name of service have artificially jacked up their prices.

An ultimate method to make drugs affordable would be to eliminate the drug coverage from the mutually subsidized healthcare system. Political and economic pressure would be tremendous. Pharmacies will have to sell drugs at affordable prices otherwise no one will buy them. Everyone will pay real prices. There will be brouhaha about this thinking but this is an ultimate method to make drugs affordable. Patients will also have to make life style choices. Such an effort would be a major disruption to the US economy. 

Drug affordability is a painful issue and has been ignored for a longtime. In mutually subsidized healthcare system prices have risen under the guise of convenience. It needs to be addressed. Even the most financially blessed feel the pain with current drug and healthcare prices.  

Girish Malhotra, PE
EPCOT International


  1. Koons, Cynthia, Why We May Lose Generic Drugs, Bloomberg Businessweek, April 11, 2018, accessed April 18, 2018 
  2. Sood, N; Shih, T; Van Nuys, K; Goldman, D; The Flow of Money Through the Pharmaceutical Distribution System, June 14, 2017, Flow of Money Through the Pharmaceutical Distribution System, Accessed March 1, 2018 
  3. Grant, Charley, Hidden Profits In the Prescription Drug Supply Chain, The Wall Street Journal, February 26, 2018, Accessed February 27, 2018 
  4. FDA Drug Shortages, https://www.accessdata.fda.gov/scripts/drugshortages/ Accessed April 24, 2018
  5. Ross, Casey: Amazon failed to disrupt the prescription drug business with Drugstore.com. Could a second try succeed? statnews.com, April 26, 2018, Accessed April 26, 2018 
  6. Leading U.S. Health Systems Announce Plans to Develop a Not-for-Profit Generic Drug Company, www.businesswire.com, Accesses March 1, 2018
  7. Triple Threat: Amazon, Berkshire, JPMorgan Rattle Health-Care Firms, The Wall Street Journal,  January 30, 2018, Accessed January 31, 2018
  8. Malhotra, Girish: May Day May Day: Can Someone Help and Lower Drug Prices?, Profitability through Simplicity, May 1, 2015, Accessed May 1, 2018
  9. Creative Destruction, https://en.wikipedia.org/wiki/Creative_destruction, Accessed April 26, 2018
  10. Malhotra, Girish: Opportunities to Lower Drug Prices and Improve Affordability: From Creation (Manufacturing) to Consumption (Patient), Profitability through Simplicity, March 9, 2018, Accessed April 25, 2018

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 
      Formulations  

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
1
500
                 182,500
Batch
One or More
200 *
0.1
                     7,300
Batch
One
10
100
                 365,000
Batch
One or More

100
50
              1,825,000
Batch or Continuous
Could be a single continuous plant but generally batch
500
20
              3,650,000
Continuous

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

Formulations:

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.  

Complexities:

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
1
Tablets per hr.
200,000
API needed Kg. /hr.
0.20
Excipient Kg. /Hr.
3.85
API+ Excipient Kg. /Hr.
4.05
Tablets needed millions per Yr. 
18,250

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