Traditions, their preservation and change, are part of human heritage. They provide comfort until a “creative destructionist” comes along and tips over the apple cart. A recent Wall Street Journal article¹ mentions “continuous processing” as a way to bring about change to pharmaceutical manufacturing. The benefits are enormous but we have to concede that we will need to rethink and modify the current business model, operating philosophies, process equipment and regulations. Changes will be needed to the current landscape and that may not be easy.

The application and adoption of different manufacturing technologies and operating philosophies is an uphill task in pharmaceuticals. Active pharmaceutical ingredients (APIs) can be formulated continuously but as discussed later will require additional work to suit the dose and demand needs. Selective application of continuous API manufacturing is definitely possible.^{2, 3, 4, 5}

This article reviews the business and process considerations for continuous processes. They are very different for the manufacture of APIs and their formulations. Any and every improvement from the current practices will lower product costs, make processes sustainable, improve product quality and profitability and expand the patient base. Companies could through improved batch and continuous processes lower global pharma costs by as much as $200 billion dollars per year6 and add close to a billion patients on a global basis to the customer base that cannot afford drugs. An unrecognized benefit of the continuous processes is the flexibility they offer to ramp production up and down to meet varying demands of drugs. Such processes can alleviate shortages. 

Current Reality
Unless there is a very compelling justification, pharmaceuticals will not change their API manufacturing and formulation processes for the existing products because the changes have to be approved by the regulatory bodies.⁷ Regulations as they exist freeze⁸ the processes once submitted/approved. No one wants to spend money for the perceived financial gains even if they are significant because the drug performance has to be reconfirmed. Associated re-approval costs are unknown and thus are a deterrent. We have to accept the current reality. However, we still need to do our best to innovate new manufacturing technologies. 

What is Continuous?
Continuous processing is being practiced in many industries including pharma’s older cousin—the chemical industry—for more than sixty years. Before we push “continuous” on any aspect of pharmaceutical manufacturing, one needs to understand the definition of continuous. A continuous process operates 24 hours per day, seven days per week and 50 weeks of the year with two weeks of holidays. Such an operation would be producing quality products for 8,400 hours per year. Industry generally takes 15% downtime for planned maintenance and unscheduled shutdowns. This means 7,140 hours being available to produce a single product per year. Anything short of these operating hours is not a continuous operation by classical definition.

An important aspect of a continuous process is that if a process in total involves multiple steps, each step has to be operated as rest of the process for the times defined above. A process would not be called a continuous process if it operates e.g. 500 hours once or twice per year and shut down for rest of the time of the year or some other product is produced in the same equipment. Such an operation might fit certain operating philosophy but does not fit the continuous process definition. An “on and off” process is similar to a batch process and will suffer from the wrath of the regulations.

Continuous processes are not mentioned in FDA regulation texts. However, cGMP practices will always be necessary. It is an excellent opportunity for the companies operating such processes to show how they can create processes that require minimum regulatory oversight by producing quality products all the time.

Going from batch to continuous in pharma demands that the pharmaceutical industry think differently9 about the manufacture of APIs and their formulations. Understanding of science, thoughtful application of applied science along with business innovation is necessary. Careless attempts will result in failures and will give naysayers an opportunity to say, “I told you so”, and will result in API manufacturing and their formulations staying inefficient with patients picking up the tab through mutually subsidized systems or from their own pockets.

Current Traditions and Landscape
It would be worth reviewing why the current traditions and regulations developed and why we are comfortable in the current landscape.

We have to recognize that the active pharmaceutical ingredients are specialty/fine chemicals that have a disease curing value. Since the reactive molecule chemistries and processing methods—unit processes and unit operations—are the same for majority of the chemicals, pharma industry very wisely used the available processing equipment. It is my conjecture that some of the following factors influenced manufacturing decisions:

1. Since the pharmaceutical companies originated in then developing countries—now the developed countries—the majority of the market was in these countries. Lack of drug affordability led to subsidized healthcare programs. Usage increased. Still the market most likely constituted less than 25% of the global population. Only rich patients, a very small population, of the remaining 75% could afford the drugs and paid from their own funds.
2. Since the drugs are used in varying milligram quantities, annual API quantities needed for the population are significantly lower than traditional chemicals. Pharmaceutical companys’ focus was to get the product to the market rather than have cost effective and innovative manufacturing processes. As a result, to assure product quality, many of the regulations and guidances came about.
3. APIs were formulated using traditional unit operations that were used in the chemical industry.10 Processes for dispensable dose compaction and ease of consumption developed as better excipients (chemicals) developed.
4. Since API manufacturing and their formulation are batch processes, testing methods were developed to meet the needs of the time. Lack of command of the processes led to rigorous in-process testing resulting in supply chain issues and inefficient asset utilization. The need for simple, repeatable and reliable processes that delivered defect-free quality products the first time were never a must. Since drugs were needed to extend life, their cost was not a consideration.  
5. Focus of pharma companies was to develop drugs for the diseases that were spreading rather than improving inefficiency of manufacturing processes as the focus was life extension rather than making drugs affordable.

All of the above works well for brand drugs and fulfills the need. Additional factors e.g. WTO agreements and brand drugs becoming generic either due to patent expiration or being nullified have led to significant landscape changes. As a result, the number of companies producing APIs and formulating generic drugs has dramatically increased.

In addition, with lower production volume compared to brand volume most of the producers use manufacturing methods that are equally or more inefficient. Since the selling prices compared to branded products are lower, a misconception has prevailed that generics use better manufacturing technologies and business practices. Some companies have developed better methods but their number is small. To retain profitability short cuts taken can affect overall product quality. Regulatory compliance and quality issue incidents have increased with time.

Increased numbers of brand and generic drug suppliers have made regulatory compliance and monitoring difficult. Regulatory bodies through regulations, directives, guidances and harmonization efforts have tried and are trying to cajole the industry to innovate their manufacturing practices so that quality drugs are produced from the onset rather than through repeated analysis. Lack of processes that produce quality drugs with minimal post-production analysis is costing the global healthcare system as much as 25% or more of the global revenue.¹¹ Unless the industry takes a self-look at its practices, not much will change. Another factor that has deterred the pharmaceutical industry from self-examination is the revenue they generate measures their performance rather than how many people can afford their drug. Drug Value Index¹² could be used as a measure—a lower index number would indicate widespread use and affordability of the drugs. 

Process Development Considerations for Continuous Processes
A maverick company should review the existing brand/generic high consumption volume drugs for their processes and manufacturing methods. Companies can also use the current selling prices, supply chain margins and processing chemistries and methods to reverse calculate the opportunities they have for the high volume generics.¹² Such an exercise defines opportunities. They could also bring to fore what are the best process technologies and what can be simplified/improved to create possibilities of continuous processes. If such a company decides to commercialize some of these products pharma’s global landscape could become very different from what it is today. 

We all understand value and benefits of continuous processes but going from batch process that is developed in the laboratory to a commercial continuous process requires many considerations. Each chemist and chemical engineer along with businessperson at some point has to use, review and incorporate the following in commercialization of their products:
1. Process chemistry
2. Process and its economics
3. Product volume
4. Equipment
5. Safe exploitation of science
6. Safety considerations
7. Sustainability

Process of commercialization has to be envisioned and planned from day one of the process development of the new molecule. It has to be completed before the active enters the clinical trial phase. If not done by then the regulatory requirements will discourage changes and innovation. The question remains: “Is a pharma insider or an outsider willing and ready to change the landscape?”
Using what is outlined I believe that process perfection and the product quality will be so high that many of the regulatory requirements and guidances may not be necessary and that would be something beyond anyone’s imagination.

Be a reactive (API) or a blending (formulation) process, significant progress has been made in the last one hundred years to have an excellent understanding and command of the processes that are safe and sustainable for the desired production volume. The difference between batch vs. continuous processes besides their production volume and operating time is that in batch process quality is tested in product at various steps whereas in a continuous process quality is built in. Final product quality checks are necessary in both methodologies.

In the process development phase all of the work is done in laboratory using traditional labware. This is essential as it defines the process parameters for the best laboratory process yield. Product volume and process define equipment needs. In general first preference for the manufacture of reactive and blended products is to use the existing available equipment.

As the product transitions from the laboratory to scale up to commercial production many of the issues that relate to product quality and regulatory bodies shape and take hold. In the chemical industry—pharma’s older cousin—regulatory issues intervene in a product’s life but not to the extent they do in pharmaceuticals. In pharma, once the product enters the clinical testing phase process changes become progressively difficult, expensive and cumbersome. As a result, processes are frozen.

Factors that do influence the process selection—batch vs. continuous—for the API and formulations are drug dose, global product demand and number of producers. Table 1 is an illustration of drug dose and the resulting process for the API. Under the current equipment configurations API for 1 and 10 mg would be most suited for batch processes. Ideally a continuous process should produce API for 100 mg for ten million patients. However, in the current business model this API most likely would be produced in multiple plants. Every batch process would most likely be inefficient—low yield, poor asset utilization with supply chain and logistic issues—and possibly have lower overall yield¹³ compared to a single continuous plant. 

Lower volume APIs could be produced using continuous process. However, process, type of equipment used and operating philosophies will have to be very different from the current thinking. Economics of such processes and operations will have to be justified. Potential for campaigned continuous process could be feasible if similar chemistry could be used in the same process equipment. Asset utilization would not be optimum.  

Table 2, an illustration, reviews various formulations options. Readers can use similar analysis to rationalize their formulation options—85% formulation yield and on-stream-time is assumed. 

For the last one hundred years companies have been formulating and packaging tablets. We have sufficient industry experience to formulate and produce quality tablets. We also have abundant knowledge about the mutual physical behavior of the components that go in the formulations. We also know how to apply the science to process development and design. Still unless constant attention is paid to the process through repeated quality checks, product quality slips.

It is my conjecture that the pharmaceutical industry has never been challenged to overcome the status quo or not felt the need to have operational excellence by applying principles of engineering and science to commercialize efficient formulation processes. Commercial formulation equipment and technologies are available to deliver the dosages needed in Table 2. It is up to the pharma companies to decide if they want to capitalize on the available options to improve their profits and deliver consistent quality products.

I am dismayed that we can send men to the moon and bring them back safely but cannot blend excipients and APIs to produce quality drugs on an ongoing basis without repeated testing. We have relied on “in-process” testing to create quality drugs. It is the industry’s responsibility to correct this anomaly. The question is: “Are we up to the challenge?”

The presentation of Vertex’s continuous formulation in the Wall Street Journal article¹ operating at 100,000 tablets per hour is interesting. It reaffirms availability of high production rate equipment. Analysis in Table 3 suggests that either the production rate is misquoted in the article, or Vertex has overdesigned a plant or their operating regimen is not discussed. The API needed for Kalydeco, the cystic fibrosis drug from Vertex, is be about 13,000 kg/year. A batch process would produce this. It is my thinking that they have invested in the plant and they will be producing different drugs for their allocated time on a campaign basis. 

It is essential that chemists and chemical engineers consider and incorporate how they can exploit physical properties of the chemicals¹⁵ involved and produced to simplify the process. These traits are not taught but are a combination of our imagination, experience and creativity. Use of multiple solvents has to be limited. Many would disagree but for simplicity, process costs and sustainability this is necessary. Since this is practiced by the chemical industry, it can also be done in pharmaceuticals if we make the effort.

Traditionally chemists and chemical engineers consider and use reactors and vessels that are available to us. We need to consider how and what all needs to be done to minimize the batch cycle time and improve process yield by exploiting lab developed operating parameters. Minimized batch cycle time nudges the process from a batch to a continuous process. In this effort consideration has to be given to use alternate equipment or use the existing equipment in the alternate way.

In recent times micro-reactors are the new buzz in reaction equipment. They are being touted as having the potential to facilitate adoption of continuous processing for the manufacture of APIs. These are expensive and at this point a laboratory curiosity. In addition, in a commercially profitable business product is produced in kilograms per hour and not grams/micrograms per hour.
Plate and frame heat exchangers have been around for more than sixty years. Such exchangers of proper metallurgy work extremely well and can be readily used. They are ideal and economic for large-scale production. We used them in our processes in the early seventies. I want to re-emphasize that running a single step for short time does not make the whole process a continuous process.

In order for any API or the formulation to be produced using continuous processes many of the factors discussed above have to have “hand and glove fit”. Due to regulatory constraints for the existing products continuous processes can be commercialized only for new brand drug processes. Incorporation of continuous processes for API manufacture and their formulations would result is a business model that is very different from the current model.

Academia^16,17 has done excellent work on improving yield and chemistries of some of the antiretrovirals. They are prime candidates for commercialization of continuous processes. A maverick company can commercialize continuous processes for Omeprazole³, Modafinil⁴, Metformin hydrochloride^5,18, Hydrochlorothiazide18 and some of the antiretrovirals to name a few.
These fit the criterion described earlier. Their commercialization will have to go through a rigorous process of convincing regulatory bodies of drug efficacy and performance and that could be a deterrent. Economies of scale and profitability will be the driver.

Conclusion
Continuous processing for the formulations can be easily done. Judicious review of the pharma landscape will show us many opportunities. Since the volumes of APIs are not conducive to year round production, alternate strategies could be considered. Use of modular equipment could be a possibility. They could come from single API line(s) at the same plant. Business strategies will be very different from the current model for such plants. 

Continuous processes will make drugs affordable to a significant patient base that cannot afford drugs or have to choose between food and life extending drugs.¹⁹ Pharma will see higher profits due to better economies of scale. Continuous processing will also reduce the excess capacity pharmaceuticals have⁵ because the production can be ramped to meet the demand.

Pharmaceuticals need process centricity and it will drive companies to quality and operational excellence rather than live with regulation centricity.²⁰ Financial justification for manufacturing innovation exists.²¹ Without effort nothing will change.

A maverick company should review the existing brand/generic high consumption volume drugs for their processes and manufacturing methods. Companies can also use the current selling prices, supply chain margins and processing chemistries and methods to reverse calculate the opportunities they have for the high volume generics.¹² Such an exercise defines opportunities. They could also bring to fore what are the best process technologies and what can be simplified/improved to create possibilities of continuous processes. If such a company decides to commercialize some of these products pharma’s global landscape could become very different from what it is today. 

There is a distinct opportunity for companies to increase their profits by double digits if they selectively implement continuous processing strategies in their API manufacturing and formulations. The landscape will definitely be different, as companies with the most competitive technologies will benefit the most. In addition, regulatory and trade barriers that exist and are created by countries would have to be overcome while global drug regulatory compliance would be greatly simplified. The benefits of lower healthcare costs, higher revenue due to a larger patient base and better quality drugs would be significant.

A maverick company, 23andMe²² has entered the pharma drug discovery industry using its technologies. My hope is that they will also look into and commercialize better manufacturing technologies. That would be a game changer. 

References

1. Drug Making Breaks Away From Its Old Ways, http://www.wsj.com/articles/drug-making-breaks-away-from-its-old-ways-1423444049, Accessed February 8, 2015
2. Malhotra, Girish: Why Fitting a Square Plug in a Round hole is Profitable for Pharma and most likely will stay? Profitability through Simplicity, http://pharmachemicalscoatings.blogspot.com/2014/08/why-fitting-square-plug-in-round-hole.html, August 1, 2014, Accessed February 24, 2015
3. Malhotra, Girish: Alphabet Shuffle: Moving From QbA to QbD – An Example of Continuous Processing, Pharmaceutical Processing, http://pharmpro.com/Articles/2009/03/Alphabet-Shuffle—Moving-From-QbA-to-QbD/, February 2009 pg 12-13
4. Malhotra, Girish: Review of Continuous Process for Modafinil, Continuous Processing in the Chemical and Pharmaceutical Industry II, 2009 AIChE Annual Meeting, November 10, 2009, Nashville, TN.
5. Malhotra, Girish: Chemical Process Simplification: Improving Productivity and Sustainability, John Wiley & Sons, February 2011
6. Malhotra, Girish: Are The Savings of $120-$150 Billions Worth Having? http://pharmachemicalscoatings.blogspot.com/2012/08/are-savings-of-120-150-billions-worth.html, August 20, 2012 (Savings were revised up to $200 billion.) Accessed March 3, 2015
7. Manufacturing the future – The next era of global growth and innovation, McKinsey & Co. November 2012, pg 54
8. Singh, R etal: Flexible Multipurpose Continuous Processing of Pharmaceutical Tablet Manufacturing Process http://www.gmp-compliance.org/daten/download/shortpaper_continuousprocessing_muzzio.pdf, Accessed March 2, 2015
9. Think Different, https://www.youtube.com/watch?v=nmwXdGm89Tk, Accessed February 18, 2015
10. McCabe, Warren L. & Smith, Julian C: Unit Operations of Chemical Engineering, McGraw-Hill & Co. 1967
11. Cost of Poor Quality, www.juran.com/elifeline/elifefiles/2009/09/Cost-of-Poor-Quality.ppt, Pg 9, Accessed Feb 20, 2015
12. Malhotra, Girish: A Blueprint for improved Pharma Competitiveness, Contract Pharma, http://www.contractpharma.com/issues/2014-09-01/view_features/a-blueprint-for-improved-pharma-competitiveness/ Sept 2014, pgs. 46-49
13. Shah, Vibhakar: PAT, QbD and Process Validation – The Enablers of Pharmaceutical Quality Assurance, CASA/FDA Pharmaceutical Industry Seminar, May 20, 2011, pg 6, Accessed March 3, 2015
14. Cystic Fibrosis population worldwide http://www.cfww.org/about/article/400/What_is_Cystic_Fibrosis Accessed February 24, 2015
15. Malhotra, Girish: Focus on Physical Properties To Improve Processes, Chemical Engineering, Pg 63-66, April 2012
16. Brown, David H. et.al: Process Improvements for the Manufacture of Tenofovir Disoproxil Fumarate at Commercial Scale, Organic Process Research & Development 2010, 14, 1194–1201
17. Longstreet, Ashley R.: Investigating the continuous synthesis of a nicotinonitrile precursor to nevirapine, Beilstein J. Org. Chem. 2013, 9, 2570–2578
18. Malhotra, Girish: Strategies to Enhance API Manufacturing Processes, Business Insights Ltd., March 2011
19. Malhotra, Girish: Drug Prices: Food vs. Medicine – A Difficult Choice for Some, http://pharmachemicalscoatings.blogspot.com/2011/06/drug-prices-food-vs-medicine-difficult.html, June 16, 2011, Accessed March 10, 2015
20. Malhotra, Girish: Regulatory Compliance vs. Operational Excellence: What Should Happen First? http://pharmachemicalscoatings.blogspot.com/2015/02/regulatory-compliance-vs-operational.html February 3, 2015
21. Malhotra, Girish: How to Justify Innovation and QbD in Manufacturing, http://www.pharmamanufacturing.com/articles/2015/how-to-justify-innovation-and-qbd-in-manufacturing/ May 4, 2015
22. 23andMe to Use Genetic Database for Drug Discovery http://www.wsj.com/articles/23andme-to-use-genetic-database-for-drug-discovery-1426161601?mod=WSJ_hpp_MIDDLENexttoWhatsNewsFifth accessed March 12, 2015

---

Girish Malhotra, president and founder of EPCOT International, has more than 45 years of industrial experience in pharmaceuticals, specialty, custom, fine chemicals, coatings, resins and polymers, additives in manufacturing, process and technology development and business development. girish@epcotint.com; Tel: 216-223-8763