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In the last SIX weeks, Charles Darwin’s “Theory of Evolution”, which occurred over millions of years has been replaced by “Reality of COVID-19 Revolution”.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

Strategies to Increase Generic Drug Competition and Bring Manufacturing to The United States of America

US FDA recently finalized “Guidance for Industry on Applications for Drugs with Inadequate Generic Competition” ⁽¹⁾. and it tells us it is the same play with different buntings. This guidance/process is totally inadequate as it is mired in FDA’s current lethargic and controlling practices. It renames the existing ANDA approval process and suggests it will create competition. However, except for minor tweaks and window dressing it is no different from what has been and is the practice.

FDA has a unique opportunity to create a legacy, bring manufacturing jobs home and address national security issue dues to potential drug shortages. It can also at the same time let the companies innovate manufacturing technologies, lower manufacturing costs, improve profits and improve affordability. Unless a process of “nondestructive creation” outlined below is adopted and implemented, the new proposal is a useless exercise of no value. In the outlined proposal there will be challenges but compared to sending man to the moon, the process would be a cake walk. There is no financial relationship with any entity. 

Following proposal/road map will not only create generic competition but also assure continued strategic drug supplies to the residents of United States. Under this scenario FDA has to grant or deny ANDA applications in 90 DAYS from the date of filing if they are properly filled and submitted ^(2,3). For this to come to fruition FDA has to create ANDA a simple filing process and environment. FDA would use the current fee structures for ANDA application filings and approvals. 

For 90 day approvals to happen FDA has to tell the industry the exact information it needs so that the ANDA can be granted or denied in the allocated time. Application will be equivalent “process operating instructions” given to any applicant filing ANDA and if followed as designed, will result perfect application (quality product) that will be approved 90 days or less. With any filing applicant guarantees that is will produce quality products.

Such filing process will be equivalent to FDA writing operating instructions that any operator (company) can follow to create a perfect product (ANDA application). I equate this exercise to be QUALITY BY DESIGN operating instructions. If any applicant company decides to produce the API or formulate in the United States 

US Government should give companies preferential ANDA approval time of 30 days vs. the proposed 90 days which includes inspection if they manufacture drugs in the United States. US has used such preferential treatments in the past ⁽⁴⁾.  

Regulators and companies cannot have any meetings prior to filings to address/answer any questions. Once the application is filed no new additional information except for minor clarifications can be asked by the regulators. 

Companies participating in this process have make sure that they will produce the quality product that has been approved by US FDA and follow FDA cGMP requirements on continued basis. If on random testing or inspection their products in US market does not meet quality specifications which they had committed to in their granted application, NO 483s will be issued and their production shut down for the next TWO years.

FDA’s filing instructions (operating instructions) that would be detailed but general enough to apply to every API and formulations application ^(5,6) . It will necessitate that FDA personnel preparing such instructions have complete understanding of API and formulation processes. Once such instructions are prepared they will have to be internally tested by FDA reviewers to make the application perfect.  This would be equivalent to operators at a manufacturing site testing the operations instructions to see if they are able to produce expected quality product. If not, the processes would need to be repeated till they produce perfect quality product.

Following time table would be followed for ANDA submissions and their grant/denial. 

Plant in USA		Plant outside USA
Day 1	Application arrives at FDA	Day 1	Application arrives at FDA
Day 7 from the filing date	FDA informs the applicant company for completeness or asks for missing information or clarifications. If no additional information is needed the review process continues.	Day 15 from the filing date	FDA informs the applicant company for completeness or asks for missing information or clarifications. If no additional information is needed the review process continues.
Day 15 from the filing date	Company submits the needed information. Review process continues. Plant inspection is scheduled.	Day 45 from the filing date	Company submits the information. Review process continues. Plant inspection is scheduled.
Day 30	Company is granted or denied the ANDA application	Day 90	Company is granted or denied the ANDA application

Girish Malhotra, PE

President

EPCOT International

1.     Competitive Generic Therapies Guidance for Industry , March 14, 2020 

2.     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 15, 2020

3.     Malhotra, Girish: What Is Needed for a Regulatory Approval of NDA/ANDA Filings in 90 Days? Profitability through Simplicity,October 24, 2018 Accessed March 15, 2020

4.     Coronavirus shows US needs to restore pharmaceutical production — in Puerto Rico, New York Post, March 7, 2020 Accessed March 16, 2020 

5.     Malhotra, Girish: What Is Needed for a Regulatory Approval of NDA/ANDA Filings in 90 Days?, Profitability through Simplicity, October 24, 2018

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

ONE PAGE Road Map to Reduce Drug Shortages, Assure Quality and Improve Affordability

Three entities are involved to make above happen. Each has to be on top of its game to provide necessary quality drugs all the times. This might seem to be an easy task but the reality is different. Each has to operate as a well-oiled machine to deliver quality products. There is no financial affiliation.

For simplicity, each entity has to manufacture its products to be a quality product. If the product has to be re-worked for quality product, entity has failed. Many might not like my equivalence of tasks each entity takes to manufacturing. In the manufacture of every product, each entity has to practice sequential steps precisely to produce their products. Same has to happen for filing or manufacture or distribution. Steps have to be precise so that anyone can follow them.  

Focus is on drugs (Brand and Generics) that have been approved. Process starts with FDA, HHS, CMS (regulators) simplifying and holding every entity including self, responsible for their products. Instead of explaining shortcomings, I am elaborating expected deliverables ^{(1, 2)} and lack thereof for each entity. Road map outlined simplifies processes and lets the companies innovate to improve affordability and improve their profits. 

Each entity will vigorously defend their turf, would not want to change the status quo. They will seek legislative interference to make sure such simplification and accountability does not interfere their “cash cows and habit of procrastination” to do the right things. Actually, done right, “road map” will improve product quality, profits and revenues. It will be an excellent example of “Nondestructive Creation” and have far reaching impact. 

Regulators & Regulations	API & Formulations	PBMs & Allies
·       ANDA filing and approval process (are process design) has to be precisely defined (= manufacturing steps) so any company (operator) follows them will meet cGMP requirements and produce quality products. Filer can get an approval in 90 days or less.   ·       If FDA instructions cannot be followed and it needs additional information from the filer, it suggests ANDA filing process design is a QbA process and is not a QbD process, as preached by FDA. ·       90-day approval would encourage competition through better technologies and economies of scale. It will also reduce shortages. This should be encouraged and promoted. ·       FDA should stop promoting technologies where it has no live/practical experience.	·       Each Manufacturer when files for an ANDA approval, is declaring that if its application is approved, it will abide by what it has been committed (commercial) in its filing. If it cannot, they should inform FDA (regulators) of their excursions outside their commitment.  ·       If a company is cited (483), it deposits $200,000.00 (refundable). If corrections are not remedied in a verified time and sustained, a second 483 citation, FDA bars the company for FOUR years to export product to USA. Deposit is lost.   ·       Company’s products can be analyzed for its quality commitment through independent sampling. If product/s are found to be outside their committed quality specifications, company needs to let the regulators and supply chain of their infractions and stop exports to USA.	·       If PBMs and allies distribute products that are tested and do not meet established quality specifications and standards, responsible member has to pay non-refundable $500,000 per incident per drug. This will assure manufacturers and distributors are always producing and selling quality products. ·       If drugs are approved by FDA, Drug Formulary should not be necessary. Let the patients and their doctors decide which drugs will serve the need and are affordable. Formulary lists prevent price and quality competition between companies.   ·       Generic drug manufacturers should be allowed, promoted and encouraged direct sales to patients through approved pharmacies. All will compete on pricing and quality.

Girish Malhotra, PE

EPCOT International

1.    Malhotra, Girish: Drug Shortages, Quality and Prices: Who is Responsible? Profitability through Simplicity

2.    Malhotra, Girish: Pharmaceutical Quality: Concepts, Misconceptions, Realities and Remedies, Profitability through Simplicity

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 manufacturing^3-16. 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 elsewhere^3-16.  

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 optimum^18-20at 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 utilization^18,19. 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 Affair^{21, 22}initiatives, 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