Girish Malhotra, Contributing Editor06.12.18
Most pharmaceutical products, irrespective of product demand, are manufactured using batch processes. Continuous manufacturing of pharmaceuticals is possible. However, the correlation between process viability and product demand needs to be microscopically examined. Lately there has been a growing fervor among regulators, equipment suppliers, some research institutions/universities and consulting houses saying that pharmaceutical companies should use/adopt continuous processing for the manufacture of drugs. Use of continuous processes where relevant, applicable and economically justified is not a bad idea. In fact, it is a great idea. However, it is necessary that such processes are authenticated according to the established definition.1
Some batch pharmaceutical formulation processes are being called continuous processes. I hope we are not twisting the fundamentals of science and engineering, economics and common sense to claim that we are on the cutting edge of innovation when in reality, we are not. I am afraid that some of the technocrats and bureaucrats may be basking in a false sense of accomplishment. Considerable monies are being spent. Such situations can impede real opportunities when they come along. I hope there is economic and scientific justification for these efforts and the industry is not being led along a path that leads to an optical illusion.
I have shared my perspective about what is involved and what it takes to develop, design, scale-up, commercialize and manage continuous processes especially in pharmaceutical manufacturing. For my own benefit I thought it would be helpful to re-review and share what I have learned and practiced, being sure to cross every “t” and dot every “i” along the way. My observations are based on my experiences and are in no way intended to criticize or challenge the opinions and perspective of others who are involved in process design, development, commercialization and management of manufacturing operations. It is very possible that I might have missed some process design considerations.
Based on my experiences it requires all layers of a company—chemists and chemical engineers, marketing, financial analysts, supply chain professionals, quality control, maintenance and manufacturing—to think about and commercialize manufacturing processes for any chemical and related industry. Some may not want to accept it, but pharmaceutical manufacturing is a subset of the fine/specialty chemical industry. Unit processes and unit operations used in the chemical industry are also used in active pharmaceutical ingredient (API) and formulation processes. APIs are fine/specialty chemicals that have disease curing value and excipients are inert additives that along with binders create the dose that can be easily ingested.
Like any manufacturing process, pharmaceuticals have their good, bad and ugly complexities. They are not all identified here but anyone familiar with process design, development, manufacturing and profitability would understand them. It needs to be recognized that the technologies and equipment that can significantly simplify processing and lower manufacturing costs are well developed and practiced in the chemical industry. However, I feel that in pharmaceutical manufacturing regulatory constraints slow down process simplification and innovation.
Product demand dictates the type of process used and this applies to every business. Since pharmaceuticals are for human consumption there are regulatory compliance requirements that add additional complexities of how the manufacturing will be controlled.
The discussion here is focused on small molecule actives and their formulations. Biopharmaceuticals are not discussed. They are in their infancy. Some concepts used in small molecule processing can be applied in biopharma processing. However, biopharmaceuticals have to become affordable to capitalize on values of economies of scale. To get there, they have a long way to go and a different business model may be needed.
Moving along, pharmaceutical manufacturing has two components—API manufacturing and formulations—and each has to be treated differently.
API Manufacturing
Active pharmaceutical ingredients (API) are toxins and are needed in small quantities to cure various diseases. Due to the small quantity needed, their dispensation in pure form is difficult. The best dispensation method is to convert them in tablets or solutions. Tablets are generally the most convenient form.
Table 1 is a hypothetical illustration of requirements for different APIs needed per patient at one tablet per day at variable doses.
Table 1. API Manufacturing Options
Table 1 may not look like it contains much value but it is extremely important for process design, production planning and scheduling, inventory control, and product management. Profits (and losses) depend on how products are produced, commercialized and managed.
Since one kilogram of an active ingredient theoretically produces one million of one milligram tablets, a small amount of API can fulfill the demand of a large patient base. Dose and population in Table 1 determine the product demand. Chemistry and economics dictate the type of process used. Batch processes are the tradition for API manufacturing. Ways to improve productivity, product quality, profits and affordability have been discussed elsewhere.
Two of the five APIs illustrated in Table 1 (let’s assume these are generics) could be produced using continuous processes. As stated earlier, batch processes are generally the first choice until market demand increases. However, under pharma’s current business model, even if the demand increases most APIs will be produced at multiple sites by batch processes. Efforts to improve or simplify existing batch processes or transition to continuous processes are shunned. Regulations do not facilitate innovation either. Existing regulations that are focused on batch processes cannot be optimally applied to continuous processes.
We have to acknowledge that APIs are fine/specialty chemicals. Equipment and processes used are no different from non-pharmaceutical fine/specialty chemicals. The same equipment is generally used to produce different actives. Since the equipment is not dedicated to any certain API, processes are modified to fit the equipment.
APIs are toxins. Thus, thorough equipment cleaning is a must to assure that there is no cross-contamination. Due to cleaning requirements and many products being produced at the same site, asset utilization for the API batch processes is less than optimum2,3,4 at best. Global overcapacity does not help either. Chemistry similarity can improve asset utilization, but sometimes it is overlooked. A judicious review is necessary and potentially necessitates a different business model being implemented.
Formulations
Table 2 is a hypothetical illustration of the number of formulation plants, or parallel trains, that would be needed to produce at the rate of 200,000 tablets per hour for different drug doses.
Table 2. Formulation Options
Like Table 1, this might not look like much. On the contrary, besides giving us the API quantity needed it also gives us the amounts of excipients needed once they are finalized. When combined, this information gives us parameters for process design, production planning and scheduling, inventory control and product management.
Theoretically, Table 2 suggests that continuous formulation plants/trains could be used to fulfill all the demand, besides the orphan drug example. Some processes need to be continuous as economies of scale will improve profits, cater to fluctuating demands and improve affordability. Since continuous formulation operations have never been on pharma’s plate, the product requirements are generally filled by batch processes.
As stated earlier, process development, equipment sizing and command would be extremely critical. One would have to have complete control of the stoichiometry, mixing and component distribution to assure tablet uniformity. A single formulation train operating 7,140 hours per year (50 weeks x 7 days/week x 24 hours/day x 0.85: allowing 15% downtime) requires a mindset that is very different from batch operations. Such operations are very possible but my conjecture is that due to stringent regulatory, product quality demands and process development challenges, companies most likely will opt to stay with batch formulation processes. Actually, batch processes due to their continued sampling, analysis and cleaning between products can be more complex to manage compared a properly designed continuous process.
The last drug dose in Table 2 requires further attention. Due to the number of patients it is an orphan drug. The amount needed for a year can be produced in a short time—less than 10 days at a rate of 200,000 tablets per hour with very little down time. Such a process, according to the established definition, would not be called a continuous process because the equipment would sit idle until the next run. If companies, or regulators, want to call such a process continuous, are they essentially changing laws of science and engineering to propose a different definition that has not been clearly stated/proposed for public scrutiny and comment? It is ironic that certain extremely high-volume products (NSAID) could have been re-engineered to a continuous process system, but stayed with the batch process option.
Complexities
Pharmaceutical companies, like every other corporation have the goal to maximize their economic return. API manufacturing and their formulations are two distinct and different processes needed to produce a drug dose. API manufacturing is a reactive process, whereas formulations, in simplistic terms, are blending and tableting operations. Every designed and commercialized process has to be the most economic. Economies of scale and process methodology (batch vs. continuous) change the product cost dynamics: batch costs generally being higher than continuous process costs.
As stated earlier, even with using the same, or similar, unit processes and unit operations in batch and continuous processes, different thinking goes into their development, design, scale-up, commercialization and management. Since the current regulations are geared towards batch processes, different regulations will have to be developed and applied for continuous processes. It would be sensible if chemists and chemical engineers who have hands-on experience in development, design, commercialization and management of such processes advise FDA and other regulators in the creation of necessary regulations. The Manufacturing Advisory Committee that existed once should be revived to facilitate and expedite the development of regulations that could apply to continuous process. I am not sure if FDA and similar regulators have the staff with hands-on experience.
In batch processes, raw materials and intermediates are generally staged and tested for quality and use. Since continuous process are time independent, the testing of every raw material and intermediate is not possible or economically feasible. Stop-and-go opportunities do not exist for continuous processes. Every unit process and unit operation has to operate as designed. Deviation from the operating conditions would mean poor product quality, significant waste and financial loss. Absolute command of process stoichiometry and operating conditions is a must.
Due to the inherent nature of batch processes, companies in every industry sample and test intermediate samples even if QbD (quality by design) methods are incorporated in the overall design. Companies do make every attempt to minimize sampling and testing. Benefits include higher profits. However, some habits die hard and companies have to be proactive and curtail these habits.
Every chemist and chemical engineer incorporates the fundamentals of science and engineering to design and commercialize the best and the most economic process. They use existing process control technologies that have been used in the chemical/fine/specialty chemical industries for more than fifty years to meter liquids, solids and manage reactive batch and continuous processes. These work extremely well. It is a bit confusing when FDA asks companies to practice QbD methods when they are the very foundation of every process design.
Since continuous processes are time independent and processes are under control, inventories should be minimum. Intermediate inline testing in continuous processes can be done to make sure that the process is operating within the designed parameters and all is going well. Excursions outside the design limits if not caught in time can result in significant quantities of off-spec product and a financial loss.
Raw material and intermediate sampling and testing have significant impact on supply chain and production planning. Batch processes increase in-process inventories and influence cash flow. In-process testing also extends batch cycle times and negatively impacts asset utilization.2,3 Collectively they increase product cost. However, raw material and work-in-process inventories can be held to a minimum in continuous processes. Production rates can be managed to meet variable product demand.
Pharmaceutical companies, like all other manufacturing companies, have sufficient knowledge base and experience that has been used to produce dispensable tablets. Since they have been and are being practiced, I firmly believe that they can be applied to overcome every complexity of pharmaceutical manufacturing. It seems that we are bogged down in “analysis paralysis” and fear the wrath of regulators if changes are made to existing manufacturing processes without their approval.
Figure 1 is a review of a formulation option from Table 2. An assumption of 95% excipient per 5% API is made; 100% yield is used.
Figure 1.
If the equipment and technologies to commercialize a continuous pharmaceutical formulation operation exist to satisfy the demand of Figure 1—50 million patients per year—why companies have not commercialized continuous processes for such cases is perplexing. Are the regulations in the way or are the companies afraid to test new equipment and methods to simplify manufacturing methods and processes?
Companies can convert the bad and the ugly complexities to good by focusing on selected drugs and thereby create economies of scale and capitalize on everything I have discussed above. If this is done, I believe the pharmaceutical landscape will change significantly and the affordability of related drugs will improve. Most likely, a different or new business model would be needed. The recent Amazon, Berkshire Hathaway, JP Morgan alliance and Veteran’s Affairs5 initiatives, if successful, could make a difference.
Regulations add complexity to any company wanting to take advantage of economies of scale, process simplification and transitioning from batch to continuous processes. My conjecture is that no one wants to spend monies on re-approval of the products. Regulators are making attempts to simplify approval processes but there are external and internal challenges. Companies might not want to simplify manufacturing for the simple fact that they are profitable even with inefficient processes.
All said and done, it is ironic that in the last four decades technologies have been developed and commercialized that are beyond our imagination but we have not used available technologies to simplify pharmaceutical manufacturing that would benefit more than 50% of the global population. It would be interesting if reasons and causes can be identified. I believe that through creativity and imagination most of pharma’s complexities can be simplified and overcome.
References
Girish Malhotra
Contributing Editor
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.
Some batch pharmaceutical formulation processes are being called continuous processes. I hope we are not twisting the fundamentals of science and engineering, economics and common sense to claim that we are on the cutting edge of innovation when in reality, we are not. I am afraid that some of the technocrats and bureaucrats may be basking in a false sense of accomplishment. Considerable monies are being spent. Such situations can impede real opportunities when they come along. I hope there is economic and scientific justification for these efforts and the industry is not being led along a path that leads to an optical illusion.
I have shared my perspective about what is involved and what it takes to develop, design, scale-up, commercialize and manage continuous processes especially in pharmaceutical manufacturing. For my own benefit I thought it would be helpful to re-review and share what I have learned and practiced, being sure to cross every “t” and dot every “i” along the way. My observations are based on my experiences and are in no way intended to criticize or challenge the opinions and perspective of others who are involved in process design, development, commercialization and management of manufacturing operations. It is very possible that I might have missed some process design considerations.
Based on my experiences it requires all layers of a company—chemists and chemical engineers, marketing, financial analysts, supply chain professionals, quality control, maintenance and manufacturing—to think about and commercialize manufacturing processes for any chemical and related industry. Some may not want to accept it, but pharmaceutical manufacturing is a subset of the fine/specialty chemical industry. Unit processes and unit operations used in the chemical industry are also used in active pharmaceutical ingredient (API) and formulation processes. APIs are fine/specialty chemicals that have disease curing value and excipients are inert additives that along with binders create the dose that can be easily ingested.
Like any manufacturing process, pharmaceuticals have their good, bad and ugly complexities. They are not all identified here but anyone familiar with process design, development, manufacturing and profitability would understand them. It needs to be recognized that the technologies and equipment that can significantly simplify processing and lower manufacturing costs are well developed and practiced in the chemical industry. However, I feel that in pharmaceutical manufacturing regulatory constraints slow down process simplification and innovation.
Product demand dictates the type of process used and this applies to every business. Since pharmaceuticals are for human consumption there are regulatory compliance requirements that add additional complexities of how the manufacturing will be controlled.
The discussion here is focused on small molecule actives and their formulations. Biopharmaceuticals are not discussed. They are in their infancy. Some concepts used in small molecule processing can be applied in biopharma processing. However, biopharmaceuticals have to become affordable to capitalize on values of economies of scale. To get there, they have a long way to go and a different business model may be needed.
Moving along, pharmaceutical manufacturing has two components—API manufacturing and formulations—and each has to be treated differently.
API Manufacturing
Active pharmaceutical ingredients (API) are toxins and are needed in small quantities to cure various diseases. Due to the small quantity needed, their dispensation in pure form is difficult. The best dispensation method is to convert them in tablets or solutions. Tablets are generally the most convenient form.
Table 1 is a hypothetical illustration of requirements for different APIs needed per patient at one tablet per day at variable doses.
Table 1. API Manufacturing Options
Table 1 may not look like it contains much value but it is extremely important for process design, production planning and scheduling, inventory control, and product management. Profits (and losses) depend on how products are produced, commercialized and managed.
Since one kilogram of an active ingredient theoretically produces one million of one milligram tablets, a small amount of API can fulfill the demand of a large patient base. Dose and population in Table 1 determine the product demand. Chemistry and economics dictate the type of process used. Batch processes are the tradition for API manufacturing. Ways to improve productivity, product quality, profits and affordability have been discussed elsewhere.
Two of the five APIs illustrated in Table 1 (let’s assume these are generics) could be produced using continuous processes. As stated earlier, batch processes are generally the first choice until market demand increases. However, under pharma’s current business model, even if the demand increases most APIs will be produced at multiple sites by batch processes. Efforts to improve or simplify existing batch processes or transition to continuous processes are shunned. Regulations do not facilitate innovation either. Existing regulations that are focused on batch processes cannot be optimally applied to continuous processes.
We have to acknowledge that APIs are fine/specialty chemicals. Equipment and processes used are no different from non-pharmaceutical fine/specialty chemicals. The same equipment is generally used to produce different actives. Since the equipment is not dedicated to any certain API, processes are modified to fit the equipment.
APIs are toxins. Thus, thorough equipment cleaning is a must to assure that there is no cross-contamination. Due to cleaning requirements and many products being produced at the same site, asset utilization for the API batch processes is less than optimum2,3,4 at best. Global overcapacity does not help either. Chemistry similarity can improve asset utilization, but sometimes it is overlooked. A judicious review is necessary and potentially necessitates a different business model being implemented.
Formulations
Table 2 is a hypothetical illustration of the number of formulation plants, or parallel trains, that would be needed to produce at the rate of 200,000 tablets per hour for different drug doses.
Table 2. Formulation Options
Like Table 1, this might not look like much. On the contrary, besides giving us the API quantity needed it also gives us the amounts of excipients needed once they are finalized. When combined, this information gives us parameters for process design, production planning and scheduling, inventory control and product management.
Theoretically, Table 2 suggests that continuous formulation plants/trains could be used to fulfill all the demand, besides the orphan drug example. Some processes need to be continuous as economies of scale will improve profits, cater to fluctuating demands and improve affordability. Since continuous formulation operations have never been on pharma’s plate, the product requirements are generally filled by batch processes.
As stated earlier, process development, equipment sizing and command would be extremely critical. One would have to have complete control of the stoichiometry, mixing and component distribution to assure tablet uniformity. A single formulation train operating 7,140 hours per year (50 weeks x 7 days/week x 24 hours/day x 0.85: allowing 15% downtime) requires a mindset that is very different from batch operations. Such operations are very possible but my conjecture is that due to stringent regulatory, product quality demands and process development challenges, companies most likely will opt to stay with batch formulation processes. Actually, batch processes due to their continued sampling, analysis and cleaning between products can be more complex to manage compared a properly designed continuous process.
The last drug dose in Table 2 requires further attention. Due to the number of patients it is an orphan drug. The amount needed for a year can be produced in a short time—less than 10 days at a rate of 200,000 tablets per hour with very little down time. Such a process, according to the established definition, would not be called a continuous process because the equipment would sit idle until the next run. If companies, or regulators, want to call such a process continuous, are they essentially changing laws of science and engineering to propose a different definition that has not been clearly stated/proposed for public scrutiny and comment? It is ironic that certain extremely high-volume products (NSAID) could have been re-engineered to a continuous process system, but stayed with the batch process option.
Complexities
Pharmaceutical companies, like every other corporation have the goal to maximize their economic return. API manufacturing and their formulations are two distinct and different processes needed to produce a drug dose. API manufacturing is a reactive process, whereas formulations, in simplistic terms, are blending and tableting operations. Every designed and commercialized process has to be the most economic. Economies of scale and process methodology (batch vs. continuous) change the product cost dynamics: batch costs generally being higher than continuous process costs.
As stated earlier, even with using the same, or similar, unit processes and unit operations in batch and continuous processes, different thinking goes into their development, design, scale-up, commercialization and management. Since the current regulations are geared towards batch processes, different regulations will have to be developed and applied for continuous processes. It would be sensible if chemists and chemical engineers who have hands-on experience in development, design, commercialization and management of such processes advise FDA and other regulators in the creation of necessary regulations. The Manufacturing Advisory Committee that existed once should be revived to facilitate and expedite the development of regulations that could apply to continuous process. I am not sure if FDA and similar regulators have the staff with hands-on experience.
In batch processes, raw materials and intermediates are generally staged and tested for quality and use. Since continuous process are time independent, the testing of every raw material and intermediate is not possible or economically feasible. Stop-and-go opportunities do not exist for continuous processes. Every unit process and unit operation has to operate as designed. Deviation from the operating conditions would mean poor product quality, significant waste and financial loss. Absolute command of process stoichiometry and operating conditions is a must.
Due to the inherent nature of batch processes, companies in every industry sample and test intermediate samples even if QbD (quality by design) methods are incorporated in the overall design. Companies do make every attempt to minimize sampling and testing. Benefits include higher profits. However, some habits die hard and companies have to be proactive and curtail these habits.
Every chemist and chemical engineer incorporates the fundamentals of science and engineering to design and commercialize the best and the most economic process. They use existing process control technologies that have been used in the chemical/fine/specialty chemical industries for more than fifty years to meter liquids, solids and manage reactive batch and continuous processes. These work extremely well. It is a bit confusing when FDA asks companies to practice QbD methods when they are the very foundation of every process design.
Since continuous processes are time independent and processes are under control, inventories should be minimum. Intermediate inline testing in continuous processes can be done to make sure that the process is operating within the designed parameters and all is going well. Excursions outside the design limits if not caught in time can result in significant quantities of off-spec product and a financial loss.
Raw material and intermediate sampling and testing have significant impact on supply chain and production planning. Batch processes increase in-process inventories and influence cash flow. In-process testing also extends batch cycle times and negatively impacts asset utilization.2,3 Collectively they increase product cost. However, raw material and work-in-process inventories can be held to a minimum in continuous processes. Production rates can be managed to meet variable product demand.
Pharmaceutical companies, like all other manufacturing companies, have sufficient knowledge base and experience that has been used to produce dispensable tablets. Since they have been and are being practiced, I firmly believe that they can be applied to overcome every complexity of pharmaceutical manufacturing. It seems that we are bogged down in “analysis paralysis” and fear the wrath of regulators if changes are made to existing manufacturing processes without their approval.
Figure 1 is a review of a formulation option from Table 2. An assumption of 95% excipient per 5% API is made; 100% yield is used.
Figure 1.
If the equipment and technologies to commercialize a continuous pharmaceutical formulation operation exist to satisfy the demand of Figure 1—50 million patients per year—why companies have not commercialized continuous processes for such cases is perplexing. Are the regulations in the way or are the companies afraid to test new equipment and methods to simplify manufacturing methods and processes?
Companies can convert the bad and the ugly complexities to good by focusing on selected drugs and thereby create economies of scale and capitalize on everything I have discussed above. If this is done, I believe the pharmaceutical landscape will change significantly and the affordability of related drugs will improve. Most likely, a different or new business model would be needed. The recent Amazon, Berkshire Hathaway, JP Morgan alliance and Veteran’s Affairs5 initiatives, if successful, could make a difference.
Regulations add complexity to any company wanting to take advantage of economies of scale, process simplification and transitioning from batch to continuous processes. My conjecture is that no one wants to spend monies on re-approval of the products. Regulators are making attempts to simplify approval processes but there are external and internal challenges. Companies might not want to simplify manufacturing for the simple fact that they are profitable even with inefficient processes.
All said and done, it is ironic that in the last four decades technologies have been developed and commercialized that are beyond our imagination but we have not used available technologies to simplify pharmaceutical manufacturing that would benefit more than 50% of the global population. It would be interesting if reasons and causes can be identified. I believe that through creativity and imagination most of pharma’s complexities can be simplified and overcome.
References
- Continuous Production, https://en.wikipedia.org/wiki/Continuous production, Accessed July 14, 2017.
- Keeling, David, Lösch, Martin, Schrader, Ulf: Outlook on pharma operations, McKinsey & Company, 2010 Accessed March 28, 2018.
- Benchmarking Shows Need to Improve Uptime, Capacity Utilization, Pharmaceutical Manufacturing, September 20, 2007, Accessed March 28, 2018.
- Kodipyaka, R: OSD: Challenges & Improvement Opportunities, Pharma Horizon, Vol.2(1) 2018 pg 21-22 Accessed April 2, 2018.
- Leading U.S. Health Systems Announce Plans to Develop a Not-for-Profit Generic Drug Company, www.businesswire.com, Accesses March 1, 2018.
Girish Malhotra
Contributing Editor
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.
