Innovation In Pharmaceuticals: What Would It Take & Who is Responsible?

Humans from time immemorial through their imagination, creativity and different teachings have innovated in every aspect of life and things they have done. All of this should have happened for every aspect of pharmaceutical manufacturing also. However reading FDA’s PAT guidance ⁽¹⁾ [excerpts shared below] one gets the regulatory perspective and their snap shot that suggests pharmaceutical manufacturing is trailing in innovation.

I have difficulties accepting their conjecture. We need to understand the basis and come up with a potential solution to remedy regulatory supposition. It will not be easy but we need to start a discussion. Sides will be taken and that would be healthy.

Unfortunately, the pharmaceutical industry generally has been hesitant to introduce innovative systems into the manufacturing sector for a number of reasons. One reason often cited is regulatory uncertainty, which may result from the perception that our existing regulatory system is rigid and unfavorable to the introduction of innovative systems. For example, many manufacturing procedures are treated as being frozen and many process changes are managed through regulatory submissions. In addition, other scientific and technical issues have been raised as possible reasons for this hesitancy. Nonetheless, industry's hesitancy to broadly embrace innovation in pharmaceutical manufacturing is undesirable from a public health perspective. Efficient pharmaceutical manufacturing is a critical part of an effective U.S. health care system. The health of our citizens (and animals in their care) depends on the availability of safe, effective, and affordable medicines.

Pharmaceutical manufacturing will need to employ innovation, cutting edge scientific and engineering knowledge, along with the best principles of quality management. Nonetheless, industry's hesitancy to broadly embrace innovation in pharmaceutical manufacturing is undesirable from a public health perspective. Manufacturers are encouraged to use the latest scientific advances in pharmaceutical manufacturing and technology.  

1. Multivariate tools for design, data acquisition and analysis
2. Process analyzers
3. Process control tools
4. Continuous improvement and knowledge management tools

Like medical doctors who take a Hippocratic Oath, chemists and chemical engineers a take an “invisible” oath and apply fundamentals of chemistry, chemical engineering, their imagination and creativity to best of their ability to develop, design, justify and commercialize pharmaceutical manufacturing processes that are ecofriendly and produce quality products first time and all the time. They are graduates of the same schools that have sent man on the moon and back and sent Voyager and Cassini. Thus we should not doubt their capabilities. Human instinct of continuous improvement always sets in after the processes have been successfully commercialized.

There is a latent conjecture in regulatory guidance that the chemists and chemical engineers have not done the best to create the existing processes. I have difficulty accepting regulatory perspective that pharma needs to innovate. Something is a miss some place.

Any layperson reading guidance excerpts would think that the API (Active Pharmacceutical Ingredients) and their formulation processes were designed by seat of the pants rather than by incorporating fundamentals of chemistry and chemical engineering. I hope that was never the case and is not the case even today.

Could it be that the regulations are standing in the way of continued pharmaceutical manufacturing technology improvement and innovation? PAT ⁽¹⁾ guidance has few self-confessions in this regard when it suggests, “our existing regulatory system is rigid and unfavorable to the introduction of innovative systems.” Second clue from the guidance is “many manufacturing procedures are treated as being frozen and many process changes are managed through regulatory submissions”

There are few other clues, at least to me. 

1.     Regulators don’t trust company’s continuous process improvements and innovation for the existing processes on the belief that every improvement would change the product performance and its efficacy. Thus, the process has to be re-examined for product quality and performance. This admission could be a challenge.

2.     Many times chemists and chemical engineers see potential improvements only after the process has been commercial. In-house time and effort needed to prove equivalence, even if not necessary, along with paperwork needed to assure same product performance is either too expensive, cumbersome and not worth the effort as it takes too long to get the necessary regulatory approval. 

Suggestion of use of certain tools and methods mentioned in guidance is bothersome because without the use of these the basic design of a manufacturing process cannot be started. Thus, I am not sure of the rationale of the suggestion in the guidance.

Chemists and chemical engineers have the aspiration and take pride in designing processes that produces quality product from the get go. They have done this for as far back as time can tell. Quality by repeated analysis (QbA) (aggravation) has disastrous financial impact on the whole business process. One bad move can have catastrophic domino effect. It is Economics 101. Since it is being done in pharmaceutical manufacturing, it suggests that there are extraneous constraints forcing this scenario. If the business is highly profitable all ignored.    

Innovation in pharmaceutical manufacturing can only happen when the technocrats are given the freedom to innovate. However a qualification has to be attached to process improvements and that is the product quality and performance will not deviate from the approved product. With this freedom there should be string attached and that is if the performance is different from the approved product, company has to abandon the process change and if they don’t, the production has to be shut down. Only a financial constraint will be a deterrent to unscrupulous process innovation adventures. 

Reality is that the systems in place today are not conducive to pharmaceutical innovation once the processes have been commercialized. To change a process step, change has to be submitted for every product and can face the approval ordeal. Due to limited patent life brand products may not have the patent life for the change to come alive. Generics just do the best they can but then shy away for additional innovations for approval expense and delays.

If we want to have continuous innovation in pharmaceutical manufacturing then we need to change the current system. To change the current system regulatory bodies and the industry have to tango together. There has to be mutual trust from each side. Pharmaceutical manufacturing and regulatory product quality landscape will have to be re-sculptured.

Since better than 90% of the pharmaceuticals are produced by batch process, industry has become dependent on taking a sample almost after every step and check it for quality. Quality by analysis (aggravation) has become the norm even if the sample taken meets the specs. This has essentially established a culture and a business model that is very different from other manufacturing enterprises. Unlike other industries in pharma we see low inventory turns of raw materials, finished goods and intermediates. They require storage space and lead to poor use of assets. Whole business process is inefficient and cumbersome. Brigades vs. battalions are needed. Processes that are designed to produce quality product from the get go become victim of quality by aggravation process. Current business model has basically destroyed planned simplicity that works for every efficient manufacturing operation.  

I would ask another question to all associated with pharmaceuticals and that is “have we progressed with respect to innovations or are we progressing”. Most likely the answer is “no”. Regulators are telling the industry of what and how to innovate and the type of manufacturing process to use e.g. continuous processes ⁽²⁾. These are distractions. Regulatory abstinence of making suggestions on methods and types of processes that companies should use will have a very positive impact on pharmaceutical innovation.

I am not sure of the basis why the regulators are making suggestions of types of processes companies should use. Do they hands on experience in process development, design, scale-up, commercialization, justification and management experience in the manufacturing processes for products that are marketed? It takes significant rigor to make the suggestions.

Same wonderment also applies for many trade journal authors who postulate certain types of manufacturing processes for pharma. A process on paper is a speculation and is different from a lab process and miles apart from an actual commercial process. When rubber meets the road reality sinks in. My intent here is not to knit pick but face reality.

Industry knows and plays on its landscape. They know and need to justify every investment of new process technologies and every improvement. As suggested earlier, regulatory bodies need to facilitate these innovations and investments by reducing the approval time. As suggested earlier manufacturing process suggestions made by the regulators are a distraction. Most of the process methods and technologies have been existed and are used in industries other than pharma. My conjecture is lack of financial justification in the current business model along with regulations has prevented use of such processes and innovation.

If regulators want industry to innovation then they have to have a defined road map ⁽³⁾ that companies can follow for process and quality approval. Regulators need not know the process design and operating parameters. However, companies have to document every change. There has to be a time period in which companies can expect approval of their submission. Regulators have laid out the cGMP practices that companies have to follow. In a previous blog I suggested three months for generic ANDAs ⁽⁴⁾. New brand drug manufacturing approval process of 18 months or less could be a target. Such expectations will present challenges for the regulators. There has to be a trust established and if the trust is violated shutting down of the operation has to be the only recourse. 
Regulatory bodies should layout the expectations for every new product specifications in a certain specified time and let the innovators innovate. This will help and lower drug commercialization time.

Lack of trust and re-checking the checker seems to be the problem also. Such situations develop only when the deliverables change from the defined specifications because someone dropped the ball. Trust has to be earned and cannot be taken for granted. Any deviation from expected specifications and processes as suggested earlier should have strict penalty like closure of the facility with no “ifs and buts”.

To recap it is in the best interest of the industry to innovate and it should be allowed to continuously improve their existing processes even after the regulators have approved the produced products and as long as the expected deliverable quality is not compromised. Review of improvements made after initial approval should be on faith, trust and desire. If regulators find excursions outside the strictly defined boundary conditions, such operations should be shut down. Only strict financial constraint will keep everyone on their tows.  


Process of continuous improvement/innovation ⁽⁵⁾ will make drugs affordable and improve pharma revenue and profits. I just wonder why pharmaceutical industry shies away from win-win opportunities. Inaction suggests that the current business model needs change.

Girish Malhotra, PE
EPCOT International

1.     Guidance for Industry PAT—A Frame work for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance http://academy.gmp-compliance.org/guidemgr/files/PAT-FDA-6419FNL.PDF

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

3.     Malhotra, Girish: ANDA (Abbreviated New Drug Application) / NDA (New Drug Applications) Filing Simplification: Road Maps are a Must, Profitability through Simplicity, May 11, 2017

4.     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

5.   Malhotra, Girish: An Alternate Look at the Pharmaceutical World and drug affordability, Prospects, Analysis and Trends in Global Pharma, CPhI Annual Industry Report 2017, page 36-41, Accessed November 28, 2017

Who Is/Or Should Be Driving Pharma’s Manufacturing Car: Regulators or the Regulated?

Obviously the question shouldn’t be asked because the answer is clear at least to me. Manufacturers of the active ingredients and their formulators, who would be or are producing quality products with the least bit of in-process testing, should be the drivers. Done right the first time, I would call that QED (quod erat demonstrandum) from my high school geometry days. QED in geometry happens only when we understand and apply fundamentals to solve a problem.

QbD in manufacturing would be equal to approaching geometry’s QED if everyone would apply science, engineering and business basics to create the best processes. If we do not apply basics to design and manage a process, we will not have command and it will produce quality product but only after repeated analysis and/or aggravation (my connotation for “A”), an expensive proposition. In addition, repeated sampling and analysis also can become an opportunity to doctor the test results, potential 483 citations. We can placate ourselves by imagining that we are applying the fundamentals but repeated product analysis clearly suggests shortcomings.

Unfortunately, in pharmaceuticals, some would disagree with my conjecture. Why do I say that? US FDA and others few years ago acknowledged QbA (quality by analysis) “aggravation” is currently the most used method to produce quality products and suggested guidelines to cajole the pharmaceutical manufacturing to incorporate the best manufacturing technologies, alleviate QbA syndrome and move to QbD (QED practices). Noble gesture and that would have benefited companies and humanity at large, but it has not happened.

If QbD had become part of the manufacturing routine from inception, landscape would have been different. Everyone would have been presenting case studies of accomplishments at conferences and we would not be discussing PAT, QbD or QbA. Continued discussion about these three acronyms at conferences and in print suggests that what the regulatory bodies were expecting has not happened.

What has me mesmerized is that in every manufacturing and even in service businesses using the best practices and processes to deliver highest quality deliverable is the norm. However, pharma is still stuck in “QbA” mode. Companies practicing QbD have and will benefit.

Had QbD become part of every API manufacture and their formulations, in my book, the resulting manufacturing practices would have lowered costs, improved profits and reduced quality issues. We scientists and engineers take pride in our accomplishments and would be blowing our horns at the highest pitch. Noise would have been deafening. Did we fail or our work environment is/was not conducive to practice what we are taught? Do we need self-reflection? 

One of my friends in the consulting business suggested reviewing few recent articles related to pharma regulations and innovations. General discussion theme of these articles was innovation in drug discoveries, R&D, impact of price controls in Europe and regulations. Inefficiencies in drug discovery (R&D) were acknowledged but no solutions were suggested. Development and practice of the best manufacturing practices for the manufacture of APIs and their formulations was not part of the discussion.

Is manufacturing such a challenge that we are afraid to tackle or talk about the issues or we don't want to talk about them as they will reflect our shortcomings? I don't believe so. Chemists and chemical engineers have shown through example what all is possible. We have met the toughest challenges.

Only reason and rationale I can imply for living with “quality by aggravation” is that the work culture in a pharmaceutical organization is not conducive to incorporate the best practices. Why? Is it because companies are in a hurry to get the product to the market and the general belief is that once the product has been commercialized we cannot change the process? If this is the general consensus, then we are mistaken. There may be others reasons that I am not familiar with.  

FDA’s clause 21CFR314.70 does permit the process of continuous improvement after the process is commercial. However, companies improving their processes have to assure that the product performance has not changed. Reading the regulation one can see that FDA has created significant red tape and hurdles for the companies to embark continuous improvements. 

All said and done companies still have to take the lead (be the driver) to commercialize the best processes and practice continuous improvement. FDA and other regulatory bodies have to take out the hurdles that come in the way for the companies to practice fundamentals of chemistry and engineering to produce quality products i.e. eliminate quality by aggravation. 

Until companies take the lead and regulatory bodies facilitate the process, we will be talking QbA in 2025 or even later. Companies have to be held responsible for quality. Penalties for distribution of less than approved quality products have to be severe. Laws might have to be changed so that companies do not hide behind the legal system. Till the regulated take the lead the regulators will drive their life.

I re-emphasize that companies create the manufacturing processes and should be the driver/owner to deliver the best product. If they don't, regulators will muddle and best quality will not be produced at optimum cost.

Girish Malhotra, PE

EPCOT International 

Could Software Technologies be the “Creative Destructionist” for Pharmaceuticals and Chemicals?

Revolution happens in every industry but some revolutions are widely noted and others are not. Nucor Steel revolutionized the steel industry through its ”mini-mills”. They are the largest steel producer in the United States. Their electric furnaces overtook the traditional blast furnaces. It was a perturbation. Many established biggies have been dwarfed.

A quiet but fast paced evolution is taking place in the food industry. Berkshire Hathaway, Warren Buffett, and 3G Capital (Brazil) have started a revolution in the food industry by acquiring Heinz, Kraft, Burger King and Tim Horton (Canada). Nestlé Chairman Mr. Peter Brabeck-Letmathe commented, “3G and Buffett have pulverized the food industry market, particularly in America with serial acquisitions” ⁽¹⁾. Outsiders are causing changes.

Pharmaceuticals are going through their mergers and acquisitions but they are very unlike in other industries. These are not based on manufacturing technology innovations. Most are related to potential new drug or increasing market share. 

Japanese and European automobile companies led their evolution through product quality and designs. On the other hand fine/specialty chemical industry, pharma’s older cousin due to lack of technology innovation, has seen its shift from developed countries to the developing countries.

Software’s influence:

Advances in software have led evolutions all over. In recent years software has progressively added conveniences for our comfort.

In retailing, through on-line stores and social media, it has changed our purchasing behavior. Google’s venture in driverless car is well known. Apple is rumored to be looking at similar opportunities. Theranos, 23andMe, Nanobiosym are using software technologies to simplify healthcare diagnostics. Google ⁽²⁾ and 23andMe ⁽³⁾ are also involved in drug discoveries. There are other companies like Verseon who are using software to reduce time for new drug discoveries ⁽⁴⁾. I am sure NIH and pharma companies have capabilities that are used to reduce drug development time. I expect that industry outsiders might have higher success because they do not have many preconceived notions and have a fresh look using latest software modeling methods.

I conjecture that combination of software and miniaturization advances might soon be available at doctor’s office. My speculation is that a routine blood analysis would be done using a handheld device that has a sensor to read the blood not requiring a blood sample. Results would be analyzed instantaneously and patient given the most accurate treatment for her/his ailment.

We are seeing significant and increasing influence of software’s prowess in our lives. Can software’s influence percolate to innovate pharmaceutical and chemical manufacturing technologies and software could be called pharma’s “creative destructionist”? Answer would be positively yes. Pharma does need a major evolution ⁽⁵⁾ and a spring.

We need to recognize that every API and its formulation is a fine/specialty chemical that has disease-curing value and has been formulated with inert excipients and packaged for easy dispensation.

Current practices:

Fine/specialty chemical manufacturing processes can be improved and changed after commercialization. However, such changes do not happen easily for pharmaceuticals. FDA regulation 21CFR314.70 has to be followed. Current practices produce the desired drug but most of the processes are inefficient and unsustainable. Speed to market is the major cause. There is significant room for improvements. Pharma’s current manufacturing practices are about 30-40 years behind times especially from fine/specialty chemicals, its older cousin. Pharma has not had the need to change because of its assured profitability.

At present, drug patented life is limited after the regulators have approved it for commercial use. Most of the active pharma ingredients and their formulations produced use methods and processes that are laboratory work based. Laboratory practices are essentially duplicated as commercial manufacturing practices even down to how the quality is checked of the intermediates. They add to inefficiency. Generics follow similar practices. Whole business process becomes and stays inefficient.

Future practices:

There is considerable discussion about change/improvement of pharma’s manufacturing practices. For it to happen paradigm shift in process development and their translation to commercial practices is needed. Change has to be initiated and has to happen within the companies. No regulatory body can force change. In addition, it has to happen before clinical trials because change later is challenging, can be expensive and has to follow regulations e.g. FDA 21CFR314.70.

Manufacturing technology innovation change has to happen at the fundamental level and it starts when any paper process chemistry is being reviewed and is going to be tested in the laboratory for feasibility and commercial viability.

From my perspective, before we start exploring/playing with the chemistry in the laboratory, it is necessary to understand the sociochemicology of all of the chemicals and that includes solvents, intermediates and produced products. Sociochemicology is the relative behavior of individual and collective behavior of chemicals. It is dependent on their physical and chemical properties ⁽⁶⁾. Many can and will ask/say why we need to know individual and mutual behavior of chemicals.

Answer to this question is simple. Individual properties and behavior of many reactants are available but mutual behaviors are not readily available. Physical properties and behavior give us many processing clues. By knowing and understanding individual and mutual behavior, we can develop great to excellent processes. We can also manipulate and exploit sociochemicological behavior to create simpler processes. Chemical engineers and chemists understand values mentioned above. Safe handling information is also important.

Having all of the above information before we go to the laboratory can significantly cut short the laboratory process development and commercialization time. However, there is big issue and it is “we do not have all of the above postulated information about sociochemicology of every chemical involved and produced”.

Information about many chemicals is available from different sites ^{(7,8,9,10,11,12,13,14)}. There are additional sources. Physical property Information is covered in e.g. Exxon’s blue book and Hydrocarbon Processing (about 1960-1965) etc. and can be of considerable value. If information about chemicals and their sociochemicalogy (their mutual behavior) is not available, it will have to be generated in the laboratory. Chemists and chemical engineers end up generating information what they think is relevant but they may review all available options.  

We do exploit sociochemicological behavior of chemicals but to limited extent. Current and ongoing advances in software technology, through modeling, could also be tapped to create/predict sociochemicological behavior of chemicals. Modeled information about behavior of chemicals would be of great value. It could give us many different process design options that we had not considered. With this information at hand, human genius using his/her creativity and imagination along with training in chemistry and chemical engineering will facilitate development and design of the best manufacturing processes in much shorter time. Such processes will consistently produce quality products at the lowest cost. Well-designed processes could significantly lower regulatory oversight from the current levels. We could also leapfrog the process of “continuous improvement” before the potential drug/s go to clinical trials. At some time in future 21CFR314.70 might not be necessary.

Some benefits of understanding and using behavioral information of chemicals are discussed. Physical state of reactants and intermediates can be used to improve laboratory process development. We may be able to limit number of solvents used to desired two and not to exceed three. Process productivity and conversion yield will also be improved. Total number of conversion steps may be minimized. Intermediate and final product solubility information can be used to develop a better commercial process. Separation processes can be greatly improved. Reaction process kinetics can be well understood and exploited to our advantage. Unit operations and processes can be simplified. Supply chain and operations scheduling can be significantly improved. Asset utilization and total business process will also improve. Capital investment can be significantly reduced.

I may be overoptimistic but having broader scope of information could catapult pharmaceutical manufacturing processes (API and their formulations) from QbA (quality by analysis) to QbD (quality by design) from inception and eliminate “B” bureaucracy (government and internal) and “C” consternation (should we think about continuous improvement) from pharma vocabulary. Processes thus developed would have many of the following benefits.

1. Longer patent life for new molecules due to shorter drug discovery and development time
2. Lowest product cost for brand and generic drugs
3. Consistent and uniform product quality
4. Use of best technologies
5. Reduced time to market
6. Highest profits
7. Highly sustainable processes with minimum environmental impact
8. Much higher customer base allowing economies of scale advantage
9. Potential of continuous API manufacture
10. Highest possibility of continuous formulations

Outlined benefits clearly suggest that it is time to accelerate change in pharma’s process development and commercialization practices. However, if we are content with the existing practices nothing will change.

Software powerhouses can create the needed information if it has not been created and/or is in private domains. Created information will definitely improve API and chemical manufacturing and their formulation methodologies. Success here would have widespread benefits for billions and pharma landscape would be changed forever. In addition, every industry that uses chemicals will also benefit.

I firmly believe that software enhancing our understanding of chemical behavior can be a REAL “creative destructionist”. Process of continuous innovation will become way of life and change many landscapes.

Girish Malhotra

President

EPCOT International

1. NESTLE CEO: Warren Buffett just 'pulverized the food industry market http://www.businessinsider.com/r-nestle-says-taking-action-to-keep-top-slot-in-food-industry-2015-4 accessed August 25, 2015
   
   
2. Large-Scale Machine Learning for Drug Discovery, http://googleresearch.blogspot.com/2015/03/large-scale-machine-learning-for-drug.html accessed August 26, 2015
   
   
3. In Big Shift, 23andMe Will Invent Drugs Using Customer Data http://www.forbes.com/sites/matthewherper/2015/03/12/23andme-enters-the-drug-business-just-as-apple-changes-it/ accessed August 26, 2015
   
   
4. Malhotra, Girish: Are Software Technologies Going to be Pharma’s Creative Destructionists? Profitability through Simplicity, http://pharmachemicalscoatings.blogspot.com/2015/07/are-software-technologies-going-to-be.html accessed August 25, 2015
   
   
5. Malhotra, Girish: Does the Pharmaceutical Industry Need A Steve Jobs? Profitability through Simplicity. http://pharmachemicalscoatings.blogspot.com/2011/11/do-pharmaceuticals-need-steve-jobs.html November 8, 2011 
6. Malhotra, Girish: Focus on Physical Properties To Improve Processes: Chemical Engineering, Vol. 119 No. 4 April 2012, pgs 63-66

7.     Chemblink

8.     http://www.chemfrog.com

9.     National Institute of Standards and Technology

10.  Royal Society of Chemistry

11.  Merck Index

12.  Handbook of Chemistry and Physics

13.  Sigma-Aldrich

14.  National Center for Biotechnology Information

Why Fitting a Square Plug in a Round hole is Profitable for Pharma and Most Likely Will Stay?

In 2005 I had raised a question about Batch or a Continuous Process: A Choice. At that time it seemed like a logical question and still is. However, I left part of the question unanswered. Missing was the discussion of components of pharma manufacturing, API manufacture and their formulations. Generally most of the discussion about pharma manufacturing focuses on formulations. API manufacturing is treated as an orphan and is not discussed.

In this discussion I have used Synthroid, # 1 prescribed and # 59 by revenue drug from top 100 US drugs from 2013 to review both segments of manufacturing and related options. Information could be used to create a better business model that will incorporate better manufacturing technologies and move away from ‘regulation centricity” to “process centricity”. End result would be improved profits and expanded global healthcare and coverage with lower costs. If properly done global pharmaceutical landscape will change.  

API manufacturing and their formulations need to be dealt separately as the technologies involved (unit processes and operations) are different. However, they influence the total business process. First has reactive processes along with purification. Resulting products could be solid or liquid. Formulation in the simplest form is basically mixing of excipients and creating dose that delivers the expected performance and can be easily dispensed and consumed. Packaging is part of the formulation.

Why Continuous Manufacturing of API’s would be a challenge:

In the last few years many on increasing frequency have chimed in for the continuous processes for API. However, it seems like that the rational principles of chemical engineering have not been applied in coming to that conclusion. Continuous usually means operating 24 hours per day, seven days per week with infrequent maintenance shutdowns, such as semi-annual or annual. Generally 15% downtime is acceptable. Anything short of this definition is not a continuous process. Continuous process also means starting with raw materials and producing finished salable product.

The following dictate the rationality of what type of process would produce lowest cost and highest quality products.

• Product volume per year
• Process
• Equipment

In the development of a commercial process chemist/chemical engineer have to know and understand these. They can have the best process but equipment and product volume dictate the course of action. Generally the first thought is to use the existing equipment if the volume does not justify a continuous process. We all know and understand that a continuous process most of the times means capital investment.

For batch or continuous process complete command of the operating conditions and methods is necessary to produce repeatable quality product. Anything short impacts product quality and business process.

Batch cycle time exceeding e.g. 48 hours necessitates a thorough review and effort even going back to the lab bench to reduce the cycle time. Long batch processes impact asset utilization and the whole business process. Every effort needs to be made to minimize the batch cycle time. In pharma extended API manufacturing batch cycle times are normal as there is no “process centricity”. “Regulation centricity” rules and is an impediment to innovation.

Table 1 is self-explanatory and presents very interesting numbers. There are some extrapolating assumptions. It is assumed that 5% of the global population uses synthroid. This most likely is a high number. Thus the actual demand for the active ingredient would be less than illustrated.

Table 1 illustrates that at 112 microgram dose at 100% formulation efficiency about 15,000 kilograms of the active would be needed to satisfy the global demand. A continuous API plant operating [24X7X350x0.85 =7,140 hrs.] would produce at about five pounds per hour, an extremely low production rate for a continuous process. Use of currently available equipment would pose many challenges and be really trying to fit square plug in a round hole. If a continuous process plant were to be built, it will require special equipment and process controls that might not be available.

All said and done there is no justification to have a continuous plant for the manufacture of active Levothyroxine (synthroid). I have not looked into it but I am sure that today multiple plants are producing the active ingredient. Each possibly has low process yields, are inefficient, have variable site to site and batch to batch product quality. Significant and expensive manpower would be needed to have consistent quality product. In reality a single plant using a batch process would satisfy total global demand.

Synthroid (Levothyroxine) sales number and prescriptions [Table 2] presents another interesting hypothesis. We can reverse calculate the price of the active ingredient. It would be based on certain assumptions and would give us a picture of profitability at different levels. US sales per prescription per month are about $3.05. These compare to sale price of $4.00 for thirty or $10.00 for ninety day supply at Walmart and Target etc.

2013 Sales, $	2013 # prescriptions	Dosage
858,725,708	23,452,848 [One prescription per person]	There are eleven different doses between (25-200 microgram) available. To facilitate calculations an average dose of 112 micrograms has been used.
Since synthroid has to be taken every day of the year we can calculate the total micrograms needed assuming 100% formulation yield. One prescription = one patient
Total API needed, micrograms per yr.		=23,452,848x112x365= 958,752,426,240
One kilogram = 1,000,000,000 micrograms
Total API needed to serve US population, Kilograms per yr.		958.75
US population taking Synthroid		(23,452,848x100)/320,000,000* = 7% [*US population]
Extrapolating number to project global Synthroid API demand per year
Global population seven billion. Assumption 5% takes synthroid = 350,000,000
Total Synthroid global API need Kg. per year			=(350,000,000x958.75/23,452,848) = 14,308

Table 1: Levothyroxine active ingredient needed for Global and US population

Sales, $	# Prescriptions
858,725,708	23,452,848
Avg. US patient cost $ per month = 858,725,708/(23,452,848x12) =3.05
Avg. dose, micrograms =112	API, Kg needed to fill US need = 958.75 Per Table 1
Profit assumption at wholesale level	100%
Sale price at wholesale level, $	= 0.5x858725708 = 429,362,854
Formulation profit 40%
Formulation level factory cost	=0.6x 429362854 = 257,617,712
Excipient and conversion cost	70% of Factory cost
Total API Purchase price, $	= 0.3x257617712= 77,285,313
API Selling price, $ per kilo	= 77,285,313/958.75= 80,610

Table 2: Reverse calculation of Levothyroxine selling price

Reverse calculation using US sales numbers suggest that active ingredient Levothyroxine cost to the formulator should be about $80,610 per kilo. Current selling price of levothyroxine on the world market is less than $3000 per kilo. This suggests even after generous profit margins being factored in Table 2 everyone in the supply chain has significant profits. These margins also indicate that all of the inefficiency costs can be passed on and there is no incentive to improve manufacturing practices. Average sale price of $3.05 per month would considered low by US standards but it might be considered expensive in the developing countries even when it is sold at $1.00 per month’s supply.  

Formulation Processes

Since dosages are in micrograms or milligrams, one kilogram can go a long way. One kilogram can make one million of one milligram and one billion of one microgram tablets at 100% yield. It tells us that a large volume of high value product can be produced from a small quantity. Using 10,000 kilograms Table 3 illustrates different production rates. At 100% yield we can produce ten billion of ten milligram or 10,000 billion tables containing one microgram active ingredient.

Tablet dose	10 milligram	100 microgram
10,000 Kilogram	10,000,000,000 Milligram	10,000,000,000,000 Microgram
# Tablets	1,000,000,000	100,000,000,000
Hours per year using 85% operating time	=350*24*0.85= 7140
Minutes per year using 85% operating time	=7140*60= 428,400
Tablets production rate per minute	=1,000,000,000 /428,400 =2,334	=100,000,000,000 /428,000 =233,426
Production rate Synthroid, 112 microgram tablets per minute		=233,426*1.43/1.12 =298,202

Table 3: Formulation production rates

Review suggests that a single plant could produce the necessary active ingredient to fill global synthroid demand. However, it would take multiple tableting lines/sites to convert the active in salable product. Since multiple doses are needed it would be worth to have parallel tableting lines. Multiple lines would give flexibility to meet the customer demand. 

Very precise and high degree of process control is needed at every step in each line. Various technologies to produce and package tablets exist. Blending of excipients and actives to deliver a uniform product requires precise controls. 

Analysis:

Point of this exercise is not to suggest that continuous processing is dead. Each manufacturing component has to be looked at separately to see what is the best for business and patient base. Going continuous for formulations is much easier than for API. Basis is ONE kilogram active ingredient can produce ONE million one milligram tablets that will serve about 27,000 patients per year at one milligram dose.

Many companies produce same API. Processes for these APIs are generally inefficient. Square plug in a round hole scenario for such molecules will exist unless a concerted business effort is made to alter the landscape through consolidation. If we look around, out of thousands of small molecule drugs may be less than ten APIs are produced using continuous processes.

Going from “B”(batch) to “C” (continuous) is not like going to the next alphabet. It will require a significant change in business thought process. Omeprazole, metformin hydrochloride and HCTZ (hydrochlorothiazide) are some APIs that could be produced using continuous process. For that matter any API that has a global requirement of more than 350,000 pounds per year could be produced using continuous process. Breakthrough chemistry and brilliant execution would be needed. Use of any API that is produced at these volumes (350,000 pounds per year or more) suggests that their consumption could be increased if costs come down. Pharmaceutical is the largest business segment where cost reduction can increase consumption by 20-30% i.e. by billions.

I am not giving up hope for continuous processes. I hope you don't either. It will take effort.

Girish Malhotra, PE

President

EPCOT International