Remedy of US’s Drug Supply Chain Shortages and Domestic Production of Generic and Brand Drugs

USA is the largest consumer of Brand and Generic drugs. Discussion here is centered around generics as they are the largest volume (84%) ⁽¹⁾ to serve the needs of US population but is very applicable to brand drugs also. Most of the US drugs are imported. Threat of US not having sufficient supply of these drugs has been there and is real. It has been talked about and discussed for quite some time. Conversations and congressional hearings ⁽²⁾ have been held. Projects ^{(3, 4, 5)} have been initiated by HHS (BARDA) and others to alleviate problem/s have no meaningful results and the problems still prevail. From my perspective all these attempts have been a charade. There is nothing meaningful on the horizon. With potential of tariffs on drugs, US needs to wake up and remedy the situation before it is too late. 

                                                               

National Academy of Sciences ⁽⁶⁾ in its most meaningless report even suggested that US should build foreign alliances to curb shortages ⁽⁷⁾. For national security reasons these recommendations ⁽⁶⁾ should have been questioned. Different US presidents have issued executive orders as far back as 2011 ^{(8, 9)} and nothing meaningful has resulted to reduce shortages or attain self-sufficiency. To bring pharma manufacturing home revamp of pharma’s business model, discussed later, along with US’s creativity and imagination is needed. This is critical. Since the industry is profitable need to change has never been a consideration. 

 

Why US has not made any progress in brining pharma manufacturing home when it can send man to the moon and bring him back. Pharma, my conjecture, has not addressed issue and/or may be does not understand the real root cause of the problem even after repeated discussions and attempts. Perspective presented is my own and is not influenced by any for profit and/or not for profit organization.  

 

Pharma companies are stuck in the current business mode (Figures 1 & 2) since middle of the last century. This is due to what I label as “equipment centricity ⁽¹⁰⁾” (Figure 1) rather than “process centricity ⁽¹¹⁾”. Since pharma has been profitable it considers itself invincible and no need to change its operating and business model has been on their radar. Figure 2 is the result of Figure1. 

Pharma’s “equipment centricity ⁽¹⁰⁾” i.e. fitting different chemistries in the same equipment has forced companies to follow stringent drug safety regulations and prescribed cGMP regimen. Downside has been low asset utilization ⁽¹²⁾. All the related costs become part of the product cost. It also has the highest hydrocarbon emissions per kilo of product ⁽¹³⁾. All of the related costs are passed on to the patients. Since the customer pays for the added costs, need for “process centricity ^{(11 )}” has not been a consideration.

With the prospect of tariffs on pharmaceuticals unless immediate steps are taken US population could suffer immensely. If US is really serious about bringing generic and brand drug manufacturing home, it has to emulate an effort like going to moon and/or create a consortium that has no outside political and regulatory meddling. Alternate business and operating model, not a rocket science, has to be adopted. Pharma manufacturing has to move from “equipment centricity ⁽¹⁰⁾” to “process centricity ⁽¹¹⁾”. If it does not this discussion will continue. 

 

Why Equipment Centricity:  

 

Why has the pharmaceutical industry dwelled on and is content with “equipment centricity”? The answer is simple. Since inception ^{(14, 15, 16)} manufacture of active pharmaceutical ingredients (API) and their formulations can be accomplished by modifying the processes to fit in the available existing equipment. This minimized new capital investment. With this pathway it accepts rigorous drug safety regulations and less than optimum use of processing equipment ⁽¹²⁾. “Equipment centricity ⁽¹⁰⁾” related costs are born by the patients.  

 

Process Centricity ⁽¹¹⁾:

 

This is not a new concept for the chemists and chemical engineers. It is pure and simple application of fundamentals of chemistry, chemical reaction engineering, processing and economics taught in our business, science and engineering curriculums ^{(14, 15, 16)} to create an excellent process. It is widely used in the fine/specialty chemical industry, older cousin of pharma. It is ironic that every reaction chemistry tells us how the “process centricity ^{(11 )}” works and how it can be exploited. Even then pharma lives in its old tradition of fitting a square plug in a round hole “equipment centricity ⁽¹⁰⁾” (Figure 1). 

 

By overlooking “process centricity ⁽¹¹⁾” especially in active pharmaceutical ingredient (API), pharma is not involving the “village” ^{(14, 15, 16)}from product inception. As a result it misses out on applying nuances of mutual and social behavior of chemicals, Sociochemicology ^{(14, 15, 16, 17)}, to create excellent processes. Some might consider this combination to be difficult. It is not. We are taught everything we need to know but have not fully capitalized on their value. We have the knowledge, creativity and imagination to accomplish the impossible. 

 

Path Forward:

 

If US wants to bring pharma manufacturing home, companies will have to internalize move from “equipment centricity” ⁽¹⁰⁾ to “process centricity” ⁽¹¹⁾. My estimate at least 180 days working 24/7 hours might be needed for each product provided it has the needed processing equipment, infrastructure, available raw materials, approved site and process. It is very possible that US might not have properly trained manpower for such task. 

 

In order for US to bring pharma manufacturing every “t” will have to be crossed and every “i’ will have be dotted. Brand and/or generics cannot be manufactured tomorrow in any available equipment . It will take time as the process and the facilities have to be approved. Processes to manufacture products just cannot be fitted in any available equipment. On top of it US does not have much of any raw materials needed for the drugs. Processing methods, equipment centric or process centric, have to be tested. Drug efficacy has to be tested. All of the above issues have to be dealt with and addressed. 

 

Companies interested in reducing/alleviating drug shortages and bringing pharma manufacturing to USA should be carrying the baton from product identification, process development, their commercialization and distribution. They have to transition from “equipment centricity” ⁽¹⁰⁾ to “process centricity” ⁽¹¹⁾ based model for the API and their formulations. Village ^{(14, 15, 16)} would have to be involved. This can happen by as stated earlier by capitalizing on mutual social behavior of chemicals ^{(14, 15, 16, 17)}, proper unit operations ⁽¹⁸⁾ and incorporating “process centricity” ⁽¹¹⁾. It will be able to accommodate variable volumes to meet patient needs in a properly designed plant. 

 

Simply said pharma’s marriage and addiction to “equipment centricity” ⁽¹⁰⁾ has been insurmountable and inseparable as significantly less effort is needed to commercialize a product. Had the chemical/pharmaceutical industry been “process centric” ⁽¹¹⁾ things would have been different. It would have had the agility to produce many different products with minimal investment. It is possible that the industry would not have gone “offshore” as USA would have led the manufacturing technology knowledge curve.   

 

CDMOs (contract development and manufacturing organization) and equipment suppliers will resist the suggested shift to “process centricity” ⁽¹¹⁾ based manufacturing. For their success they will have to support “process centricity ⁽¹¹⁾. Since CDMOs rely on “equipment centricity” ⁽¹⁰⁾ there should not be any surprise if US based CDMOs move overseas. It is time for pharma to consider alternate business model if it wants to bring pharma manufacturing to the largest market, USA. 

 

FDA will have to reconfigure itself and its approval processes for NDA (new drug application) and ANDA (abbreviated new drug application) by reducing their approval times to 90 days ⁽¹⁹⁾. Environmental and other regulatory approval times will have to be reworked. Every “K Street” ⁽²⁰⁾ residents would be an influencer. Legislators will have to participate in bringing manufacturing home by creating a FOUR STATE model and rejuvenating “Puerto Rico” ^(21,22) type model. It will be an added opportunity to bring jobs home. 

 

Companies (pharma and Pharmacy Benefit Managers (PBMs) will have to guarantee product quality and would have to accept sever penalties for any and every deviation ⁽¹⁹⁾. Companies will have to have total complete knowledge and command of the production and distribution process. Since every NDA and ANDA drug is FDA approved drug tiers ⁽²³⁾ have to go. They artificially raise prices. Direct sales to patients have to be allowed. Price, quality and drug efficacy based competition is the best way to reduce shortages. 

 

Unlike the past efforts that have resulted in nothing a collective thought through effort needs to be made. There will be resistance from every vested interest. 

 

Recent announcements by Eli Lilly ⁽²⁴⁾ $27 Billion, Johnson & Johnson ⁽²⁵⁾ $55 billion, Novo Novartis ⁽²⁶⁾ $23 billion are “equipment centric” ⁽¹⁰⁾ projects for their brand products. These are not going to be commercial at least for the next 4-5 years and will not produce products to fill tariff related immediate needs. Once patents for their drugs expire these investments could become the “white elephants” of no value looking for home.   

  

Simply said pharma’s marriage and addiction to “equipment centricity” ⁽¹⁰⁾ that has been inseparable and insurmountable needs to change. My conjecture is that “process centricity” ⁽¹¹⁾ effort will be a  “win-win” situation for the companies and a BIG win for the patients. Task is going to be challenging. US has never shrugged from any challenge. Let us be brave and get going.  

 

Girish Malhotra, PE

EPCOT International 

 

References:

1.     U.S. Pharmaceutical Statistics

2.     Woodcock, Dr. Janet: SECURING THE U.S. DRUG SUPPLY CHAIN: OVERSIGHT OF FDA’S FOREIGN INSPECTION PROGRAM December 10, 2019 

3.     Phlow Corporation Pharmaceutical Technology July 16, 2020

4.     DOD Awards $69.3 Million Contract to CONTINUUS Pharmaceuticals to Develop US-based Continuous Manufacturing Capability for Critical Medicines   January 15, 2021

5.     API Innovation Center  

6.     BUILDING RESILIENCE into the Nation’s MEDICAL PRODUCT SUPPLY CHAINS National Academies of Sciences, Engineering, and Medicine, 2022

7.     Malhotra, Girish: Has US lost its Business Acumen, Creativity and Imagination for its Healthcare Needs? Profitability through Simplicity, June 6, 2022

8.     EO 13588 Reducing Prescription Drug Shortages October 31, 2011

9.     EO 13944 Combating Public Health Emergencies and Strengthening National Security by Ensuring Essential Medicines August 6, 2020

10.   Equipment centric https://images.app.goo.gl/Qi2UZKqu4qHdLWvu6

11.   Malhotra, Girish: Process Centricity is the Key to Quality by Design, Profitability through Simplicity April 6, 2010

12.   Schrader, Ulf: McKinsey & Co. Operations can launch blockbuster in pharma, February 16, 2021

13.   Sheldon R.A. The E factor 25 years on: the rise of green chemistry and sustainability, Green Chemistry

14.   Malhotra, Girish: Active Pharmaceutical Ingredient Manufacturing: Nondestructive Creation De Gruyter May 2022 

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

16.   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

17.   Malhotra, Girish: Sociochemicology, May 30, 2013

McCabe W. L & Smith J. M. Unit Operations of Chemical Engineering McGraw-Hill Book Company Second Edition 1967

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

20.   K Street

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

22.   MacEwan, Arthur: The Effect of 936 May 2016  

23.   Understanding Drug Tiers Accessed October 22, 2023 

24.   Eli Lilly  April 14, 2025 

25.   Johnson and Johnson April 14, 2025

26.    Novartis April 14, 2025

 

Pharma’s Advanced Manufacturing Technologies: REALITY OR FIGMENT OF IMAGINATION

USFDA at least since 2013 ⁽¹⁾ has been promoting use of advanced manufacturing technologies (AMT) and that includes “continuous manufacturing (CM) ⁽²⁾ for the manufacture and reduce shortages of drugs ^(3,4,5). It has held various conversations and even involved National Institute of Sciences (NAS). This report “Building Resilience into the Nation's Medical Product Supply Chains ⁽⁶⁾ is a disturbing as it suggests increasing reliance through foreign relationships. 

 

FDA ⁽⁷⁾ has continued to convince the pharmaceutical industry to use advanced manufacturing technologies (AMT) but seems like no one is buying what it has been selling.

 

What are these technologies is not clear. Do AMT include manufacture of API along with their formulations or anything else? A clarification from FDA was asked from its CDER/OPPQ/Office of Policy for Pharmaceutical Quality. A very terse response was received “they will respond in several weeks”. This is especially enlightening and interesting when FDA has been touting to the world to adopt such technologies. If FDA is trying to promote adoption of better manufacturing technologies, it would be beneficial if they were more forthcoming in addressing asked questions.  

 

Even after all the conversations and congressional hearings and claims that these will reduce shortages FDA’s effort that has not resulted in any progress in commercializing AMTs at the pharmaceutical companies. This basically suggests that this effort is not going anywhere. If after effort of more than five years and millions of tax payer dollars that have been doled out to universities and other institutions nothing meaningful has happened.  It basically suggests that companies are not buying what USFDA is selling.

 

It is ironic that FDA wants companies to incorporate “continuous manufacturing (CM) ⁽²⁾” but has not shared what is its understanding and definition. In the manufacturing world there is an established definition ⁽²⁾. It would be interesting how FDA’s definition compares with the established definition. It also needs to very clearly explain what does it call “drug manufacturing”. Is it just formulation of active pharmaceutical ingredients (API) or combination of manufacture of APIs and their formulations? We have to remember that without API there is not drug. It is just a placebo. 

 

FDA has called formulation of certain cancer cure drugs (limited global population which means limited demand) as continuous processes (CM) ⁽⁸⁾. Involved companies formulate batch produced API to finished products. Since these products are formulated on stop and go basis i.e. batch production ⁽⁹⁾, the underlying question is why FDA distorting facts and calling these processes CM. Is it trying to convince the pharma industry that it needs to change its manufacturing practices? Justification and rationale are needed. Even press has been talking about CM ⁽²⁾ when they have no idea what it means. 

 

Based on formulation and compaction technologies that have been commercial and are used to produce many products, question that needs to be addressed is “why the pharmaceutical industry has not adopted established (more than fifty years) technology “en masse”. Is it lack of experience, business model or regulatory interference or being comfortable and profitable with quality by “analysis paralysis” processes? 

 

It is a well-known fact that industry invents drug products. New and/or existing technologies and methods are used produce quality products. However, FDA’s telling the industry that new technologies need to be approved ⁽¹⁰⁾ before they can be implemented is a deterrent for brand and generic drug industry. No one knows what these technologies are. businesses. With FDA’s staff having minimal to no or minimal experience in product and process development, design and commercializing any drug molecule and their manufacturing processes, it would amount to further delays from the current times in brand and generic products. This is an un-necessary interference and oversight of a company. Question is how FDA will help. 

  

Industry should be meeting the necessary drug performance criterion using the methods and processes it has developed, tested inhouse and would want to commercialize ASAP. Every product goes through three steps a) lab, b) pilot plant and c) commercial scale. This will be true for every product if it will be produced using a continuous process ⁽²⁾. Due to FDA staff’s limited experience suggested pre-approval review etc.⁽⁷⁾ will result is further commercialization delays as they have no hands on experience of process development. This will result in further commercialization delays. If the industry does not see value in this effort they will not change their  existing practices and/or consider any new technologies. 

 

USFDA has to be very clear of the pathway it wants industry to follow to implement new technologies. FDA has to layout parameters/questions regarding the technology it wants to the industry to address along with a timetable. Goal has to be commercialization of drug in minimal time after its efficacy has been recognized by the pharma company and proven. Pathway for brand and generic drug will be different. There is big gap between FDA and industry as no headway has been made to improve manufacturing technologies. Industry has to recognize financial value and they do not see it as they are profitable. 

May be it is time for FDA to consider alternate ways so that the pharma industry’s manufacturing can come to 21^st Century. It has tried to corral and impress US congress using its resources, as discussed earlier, but no one has budged. It is my conjecture that nothing will change unless the pharmaceutical industry (development and manufacturing) gets involved. They would not till they see a return. Alternate presented is my own and not influenced by any “for profit and nonprofit” organization. 

 

Pharmaceutical industry would be enthusiastic and welcoming if products produced using better manufacturing technologies could be commercialized much sooner than the current times for NDA (new drug applications) and ANDA (abbreviated new drug applications). For that to happen the triumvirate (FDA, Pharma companies, and Pharmacy Benefit Managers (PBM)) have to change the current methods. My thoughts are a stretch and will face resistance from each. Most will come from FDA and PBMs. Pharma companies most likely would like them as they will lead to shorter time needed for commercialization i.e. higher revenues and profits.  

 

FDA: 

 

FDA when it comes to NDA and ANDA approval needs to eliminate every pre-approval meetings and that includes any new manufacturing technology introduction and use templates to get information it would consider necessary for their review and approval ^(11,12). These meetings are suggestive that the applicant companies do not know and/or understand what all is necessary for approval and they have to teach FDA what is the rationale and value of their innovations. Once FDA has the knowledge, it is possible that approval times could be reduced from current times ^{(13, 14, 15)}.

 

Is FDA personnel due to lack of their experience in process development, scaleup and commercialization especially in “continuous” API and formulations using these meetings to further delay approvals. Basically this could be considered that FDA is learning on the fly what all is necessary for approval. FDA needs to create its expectation guidelines for every new (NDA) and existing (ANDA) drug each applicant company has to follow. These guidelines would be routinely updated so going forward companies. Assimilation of this suggestion will be difficult for FDA. 

 

Pharma companies: 

 

Pharma companies have to have every “t” crossed and “i” dotted when it is submitting information required by FDA for their NDA and ANDA as if they will consume first tablet that comes of the production line and their life depended on it. For continuous API manufacturing and their formulations it is very likely that pharma’s current manufacturing landscape would have to be changed ^{(16, 17, 18)}. Companies would be challenged by FDA as they might have to familiarize FDA personnel with nuances of continuous manufacturing. Not having any process development, scale up and commercialization experience this can be a challenge. Chemists and chemical engineers will need company support, a challenge.  

 

PBMs:

 

For Pharma companies to get excited about consideration and incorporation of newer and better manufacturing technologies, in addition to faster approval than current times, they should be allowed to direct market their FDA approved products by bypassing the formulary lists. Patient and physician should be deciding which approved drug they want to use. PBMs should not be interfering in patient’s life. Having a choice of drug would bring highest quality product at the best price competition to market. Competition is healthy and good for encouraged. PBMs are not required to meet quality standards. They should be held accountable ⁽¹⁴⁾.

 

Yes in the final analysis suggestions made here could be considered radical and not to the linking of parties involved. FDA has been going around with all sorts of permutations and combinations but nothing meaningful has materialized. It has not created an environment to innovate. Pharma industry has ignored FDA’s suggestions. PBMs have no interest in reducing shortages. Unless the accountability is shared by each party involved, US drug system (manufacturing, approval and distribution) have and will limp along and patient will continue to suffer. 

 

Path forward:

 

With FDA’s effort of more than eight years, no progress has been made to incorporate proven better manufacturing technologies used elsewhere in API manufacture and their formulations. Pharma manufacturers are comfortable with the current methods that have been in use from 1940-‘50s as they are profitable ⁽¹⁸⁾. PBMs have no interest in what manufacturing methods/technologies are used as they just sell/distribute drugs to patients at their partial monopoly prices. Shortages have become way of life. An outlier approach is needed if we want to reduce shortages and include better manufacturing technologies. 

 

FDA could promote the modified filing process with a stipulation that companies will have faster approvals than the current times i.e. higher profits. As part of the buy in for shorter approval time, FDA could use its legislative clout and bypass the current marketing channels i.e. formulary constraints. Manufacturers would offer the drugs to patients through alternate channels. PBMs will resist these suggestions as their stranglehold on generic markets would be influenced. 

Suggested pathway should encourage generic manufacturers to invest in better manufacturing technologies i.e. continuous API manufacturing and their formulations. If FDA’s test with generics is a success, it could be extended to brand drugs. Yes brand drug product and process information requirements for approval will be different but the current logjam of slow action will be broken. 

 

FDA would need to start the approval simplification process by creating templets that detail information needed for approval. Creation of information asking templets ⁽¹⁴⁾ could be test of FDA’s internal knowledge and competence. There could be significant internal resistance as the review and approval methods would change. FDA’s pre-meetings etc. would have to be curtailed. This would place the onus of convincing FDA to grant the approval. Companies have more to lose if they do not receive timely approval. Such a change is needed if we collectively want to simplify the age old process. To implement the suggested change FDA may have to avail congressional help, if necessary.

 

Companies may include additional information, some of it could be redundant. Excess of submitted information may help the approval process. In the proposed process FDA personnel will still have an opportunity to ask for additional information ⁽¹⁴⁾to complete the review resulting in grant and/or denial. Review and grant process will have defined time window. Once ANDA is approved certain restrictions could be placed on the filing company i.e. it cannot transfer the approved ANDA to any other profit making company in the next twelve months and it has to produce the product for sale in USA within 1-4 months of the approval. Success with generics could be applied for brand drugs.

 

Since companies will have FDA decision in a finite time rather than unknown time, they should be enthusiastic about the suggested process. They would be able to commercialize their manufacturing process innovations and get a better return on their investment. Yes in the final analysis suggestions made here are radical and may not to the liking of some  involved. 

 

FDA and US Congress have been talking and making noise but no solution has been proposed. As suggested earlier chemical engineers are not practicing unit processes ⁽¹⁹⁾ and unit operations ⁽²⁰⁾ they have been taught to the fullest extent. The process outlined ^{(16, 17,18)} will allow them to incorporate them and create excellent processes to produce quality products. It is time pharma manufacturing comes of age. 

 

Product and manufacturing process technology innovation comes from pharma companies. They do their first part but as said earlier dur to profitability they have lagged on the second part. Unless responsibility to reduce shortages is shared by each party involved, US drug system (manufacturing, approval and distribution) will continue to limp along and patient will suffer. It is time to consider better alternate processes to reduce shortages that include better manufacturing technologies and alternate drug distribution model. We have the minds and chutzpah to excel. Time is now.  

 

Girish Malhotra, PE

 

EPCOT International 

 

References:

1.     Strategic Plan for Preventing and Mitigating Drug Shortages  Accessed March 31, 2024 

2.     Continuous Production

3.     TESTIMONY OF JANET WOODCOCK, MD December 10, 2019

4.     Agency Drug Shortages Task Force October 30, 2019 https://www.fda.gov/drugs/drug-shortages/agency-drug-shortages-task-force

5.     Malhotra, Girish: Identifying the Root Causes of Drug Shortages and Finding An Enduring Solution, Profitability through Simplicity, December 7, 2018

6.     Building resilience into the Nation’s Medical Product’s Supply, National Academy of Scienceshttps://nap.nationalacademies.org/read/26420 Accessed April 22, 2022

7.   Advanced Manufacturing Technologies Designation Program, Guidance for Industry, December 2023 https://www.fda.gov/media/174651/download   

8.     Malhotra, Girish: Batch, Continuous or "Fake/False" Continuous Processes in Pharmaceutical Manufacturing,Profitability through Simplicity, July 20, 2017

9.     Batch Production https://en.wikipedia.org/wiki/Batch_production

10.  Lifecycle of an Emerging Technology Program (ETP) https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/lifecycle-emerging-technology-program-etp

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

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

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

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

15.  Malhotra, Girish: Roadmap to Reduce Drug Shortages Profitability through Simplicity October 30, 2023

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

17.  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

18.  Malhotra, Girish:  Active Pharmaceutical Ingredient Manufacturing: Nondestructive Creation DeGruyter April 2022

19.  Shreve, R. Norris: Unit Process In Chemical Processing, Ind. Eng. Chem., 1954, 46 (4), pp. 672–672

20.  Unit Operation, https://en.wikipedia.org/wiki/Unit_operation , Accessed July 11, 2017