Girish Malhotra, President, EPCOT International04.03.17
Introspection into what we do, think and create has value. It allows us to do things differently and in better ways. If we step outside the box, past experiences facilitate continuous improvement and allow for innovation to take place.
Strangely, the pharmaceutical manufacturing process domain has many acronyms that can make us, at least to me, wonder what are the realities of the landscape. All of these acronyms have made me question what is real vs. unreal. In this article I would like to share my perspective on these acronyms and their influence. Many times these acronyms are like a fashion statement. They can make simple things seem complex. If by using acronyms are we hiding behind our fears of not having command of processes? I wonder.
I am sure many glorified acronyms can be and have been created for simple mundane things. Just for discussion I will create a new acronym: Life Extension Product (LEP) for a simple necessity called FOOD. Governments have many such acronyms. I would not be surprised if a completely meaningless sentence could be written with many acronyms that only a handful of government employees will actually understand, no pun intended.
I would like to review three acronyms—two old and one new—used in Pharma today that to me are purely engineering/science and economics-based, are rational, but give the impression of complexity and sophistication. I am sure some may object to my interpretation and simplification/rationalization. However, sometimes, as said earlier, self-examination of things has value and simplifies life.
PAT
PAT stands for “process analytical technologies.”1 Chemists and chemical engineers are taught and very well know that if they do not have command of the designed process, the produced product will not have the same quality from every batch, if batch process is the process of choice. Total command of the executed process is expected. Each process has to have the same footprint no matter when and who produces the product. It is well known that lack of first time quality is expensive.
While the progress of intermediates and final product as they travel the reactive or formulation process, are tracked using various process controls and analytical methods that have become more sophisticated and accurate with time; the fundamental premise has not changed in more than 80 years. Incorporation of statistical methods started in the 60s and their use has progressed over time. Again, chemists and chemical engineers are taught and suggested their use in the process development and design.
My point is that routine methods and criterions that are necessary in every process to produce quality product have just been given a fancy name: PAT. Its use is just camouflaging something simple with more complexity, creating the illusion that it is the necessary magic that will produce quality. Many still struggle to understand and incorporate these expectations in their process designs.
QbD
QbD stands for “quality by design” and like PAT is another FDA acronym. Chemists and chemical engineers are expected to design processes that will produce quality from the get go and should not be told to do so. Anything short generally will result in economic disaster as monies and time are expended to bring off-spec product to quality or disposal unless associated costs are passed on to the customers. Repeated product testing to achieve quality is expensive [=QbA, Quality by Analysis] and impacts the whole business process. I call it “quality by aggravation.”2
Manufacturing processes
Generally batch or continuous processes are used in the manufacture of most products. Their process designs follow their protocol and their design is justified on the basis of the product need. Pharmaceuticals—active pharmaceutical ingredients (API) and their formulations—are mostly produced using batch processes.
Pharmaceutical APIs are fine/specialty chemicals that have a disease curing value and are produced via a chemical reaction or a biochemical process. From the beginning of organic chemistry, organic chemicals have been produced using batch processes. A very pertinent question needs asking, “Why batch?” The answer to this is simple. Such processes are the easiest to practice in the laboratory while being the simplest to understand and commercialize to produce the needed product.
An important fact, the needed product volume, cannot be overlooked. Small quantities of active ingredients—generally milligrams—are needed by patients. Until the patient-use threshold increases above a certain volume3 “continuous manufacturing” should never be a consideration for the manufacture of APIs. Campaigns of exact similar chemistry products could be an exception but require strategic review.
Except for few handfuls of active ingredients (e.g. acetyl salicylic acid, aka Aspirin; isobutyl-phenyl-propionic acid, aka Advil/Motrin; or N-acetyl-para-aminophenol, aka Tylenol) not many APIs were, or are produced the 24 hours per day seven days per week, 50 weeks per year, which are the requirements for a “continuous process.”4
The production of APIs in multiple plants impacts the following business elements that in turn raise product cost:
Pharma’s new buzz acronym
Continuous manufacturing processes have been used in the fine and specialty chemical industry—pharma’s older cousin—for more than sixty years. Unit operations and processes used in these are also used in pharma’s chemical reactive and blending processes.
Suddenly out of nowhere “continuous manufacturing” has become pharma’s latest buzzword because FDA has shown interest and started talking about it. A recent unsubstantiated claim has been made regarding the continuous manufacture for a drug5 that has extremely limited demand and can only be economically produced using batch process. Such claims defy engineering and business logic.
It is ironic that many of the continuous manufacturing accepting naysayers have now joined in the chorus, singing its virtues as the new “to be and to do” technology. Some publications and conferences that dreaded the words continuous manufacturing have suddenly embraced it to impress everyone. Thus our new acronym “CM” is born. I am not sure if the economics and reality of the process is really understood. Process technology and economics need to be answered and addressed6 for the plants that can produce an API continuously or formulate it continuously.
As I suggested earlier that very few APIs—probably less than 10—can be produced using a continuous process. There are many drugs that can be formulated continuously but require justification and an absolute command of the process.
Fundamentals of chemistry, chemical engineering and process controls have to apply and work more than 100% for the success of continuous processes. Technologies—blending, controlled mass-feeders, etc.—have to be tested and precisely married to deliver formulated products that are “spot on” quality specs day in and day out. Feedback process controls that have been designed, developed and used for more than 60 years have to be tested for each product. Mid-course correction in blending and tableting operations impact product specs and performance and have to be precise and understood.
Up and down side of technologies
Again, for continuous processes to succeed there has to be complete and repeatable command of every process condition, unit operation, and operating parameter that influences product quality. If done so, in due time acronyms like PAT and QbD would disappear from pharma’s formulation vocabulary.
Most of the discussion related to pharmaceutical manufacturing centers around formulations. API manufacturing is ignored and I feel it is considered a necessary orphan that just happens to be an intruder in the landscape. We have to recognize that without an API we do not have a drug.
For a continuous formulation process supply of consistent quality raw materials to operate the process producing the same drug, about 7,000 hours per year is a must. If the operating equipment producing a single drug/dose is idle more than 40% of the 8,400 hours available per year, then the operation is similar to the current batch business model. Actually the investment could be considered a waste.
Any operation that is producing more than 60% of the global API need would have much better technology giving it a cost and quality advantage. In some cases, a continuous process could produce it. API consolidation would be necessary.
Since every kilo of API produces a million tablets of milligram doses each, generally formulation plants will have to operate more hours relative to the API plant. A properly and strategically designed continuous plant could fulfill the need and eliminate the need for many contract formulation plants producing the same drug. Basically, when all is said and done, efficient and properly designed continuous API and formulation plants will result in the consolidation of a significant number of operations.
Conclusion
My reasons and rationale for putting all of the above on paper is not no discredit or challenge anyone’s knowledge and desire to embrace the best available technologies that will enhance profits, improve revenues and make drugs affordable to billions. I just want to share my perspective of the up and downside of the technologies we can practice in pharmaceutical manufacturing. Investment justifications for technologies we use or will use are a must. Blind faith equals financial waste. Adoption of a technology that might be good for a certain product does not mean that it will be good across the landscape.
Continuous manufacturing does not fit every hand. It has to be custom fitted. It is not a fashion that is economical and suits everyone’s needs. Before we all start touting the values and benefits of continuous manufacturing, of which there are many, every pencil needs to be sharpened. Every “t” crossed and “i” dotted will show the value (e.g. high inventory turns with high asset utilization) but also show the downside and the challenges, especially for the batch formulation operations. There are bold opportunities ahead and if adopted will alter the current pharma manufacturing landscape. The faint hearted will have to consider how to manage and survive in this altered playing field.
References
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.
Strangely, the pharmaceutical manufacturing process domain has many acronyms that can make us, at least to me, wonder what are the realities of the landscape. All of these acronyms have made me question what is real vs. unreal. In this article I would like to share my perspective on these acronyms and their influence. Many times these acronyms are like a fashion statement. They can make simple things seem complex. If by using acronyms are we hiding behind our fears of not having command of processes? I wonder.
I am sure many glorified acronyms can be and have been created for simple mundane things. Just for discussion I will create a new acronym: Life Extension Product (LEP) for a simple necessity called FOOD. Governments have many such acronyms. I would not be surprised if a completely meaningless sentence could be written with many acronyms that only a handful of government employees will actually understand, no pun intended.
I would like to review three acronyms—two old and one new—used in Pharma today that to me are purely engineering/science and economics-based, are rational, but give the impression of complexity and sophistication. I am sure some may object to my interpretation and simplification/rationalization. However, sometimes, as said earlier, self-examination of things has value and simplifies life.
PAT
PAT stands for “process analytical technologies.”1 Chemists and chemical engineers are taught and very well know that if they do not have command of the designed process, the produced product will not have the same quality from every batch, if batch process is the process of choice. Total command of the executed process is expected. Each process has to have the same footprint no matter when and who produces the product. It is well known that lack of first time quality is expensive.
While the progress of intermediates and final product as they travel the reactive or formulation process, are tracked using various process controls and analytical methods that have become more sophisticated and accurate with time; the fundamental premise has not changed in more than 80 years. Incorporation of statistical methods started in the 60s and their use has progressed over time. Again, chemists and chemical engineers are taught and suggested their use in the process development and design.
My point is that routine methods and criterions that are necessary in every process to produce quality product have just been given a fancy name: PAT. Its use is just camouflaging something simple with more complexity, creating the illusion that it is the necessary magic that will produce quality. Many still struggle to understand and incorporate these expectations in their process designs.
QbD
QbD stands for “quality by design” and like PAT is another FDA acronym. Chemists and chemical engineers are expected to design processes that will produce quality from the get go and should not be told to do so. Anything short generally will result in economic disaster as monies and time are expended to bring off-spec product to quality or disposal unless associated costs are passed on to the customers. Repeated product testing to achieve quality is expensive [=QbA, Quality by Analysis] and impacts the whole business process. I call it “quality by aggravation.”2
Manufacturing processes
Generally batch or continuous processes are used in the manufacture of most products. Their process designs follow their protocol and their design is justified on the basis of the product need. Pharmaceuticals—active pharmaceutical ingredients (API) and their formulations—are mostly produced using batch processes.
Pharmaceutical APIs are fine/specialty chemicals that have a disease curing value and are produced via a chemical reaction or a biochemical process. From the beginning of organic chemistry, organic chemicals have been produced using batch processes. A very pertinent question needs asking, “Why batch?” The answer to this is simple. Such processes are the easiest to practice in the laboratory while being the simplest to understand and commercialize to produce the needed product.
An important fact, the needed product volume, cannot be overlooked. Small quantities of active ingredients—generally milligrams—are needed by patients. Until the patient-use threshold increases above a certain volume3 “continuous manufacturing” should never be a consideration for the manufacture of APIs. Campaigns of exact similar chemistry products could be an exception but require strategic review.
Except for few handfuls of active ingredients (e.g. acetyl salicylic acid, aka Aspirin; isobutyl-phenyl-propionic acid, aka Advil/Motrin; or N-acetyl-para-aminophenol, aka Tylenol) not many APIs were, or are produced the 24 hours per day seven days per week, 50 weeks per year, which are the requirements for a “continuous process.”4
The production of APIs in multiple plants impacts the following business elements that in turn raise product cost:
- Asset utilization drops to as low as 50% or more;
- Manufacturing technologies are not optimum. Quality by Aggravation can be an operating norm. Conversion yields of such processes are not optimum. Significant effort and investment is required for safety and environmental compliance; and
- Supply chain and inventory turns compared to other businesses are extremely low, e.g. less than two.
Pharma’s new buzz acronym
Continuous manufacturing processes have been used in the fine and specialty chemical industry—pharma’s older cousin—for more than sixty years. Unit operations and processes used in these are also used in pharma’s chemical reactive and blending processes.
Suddenly out of nowhere “continuous manufacturing” has become pharma’s latest buzzword because FDA has shown interest and started talking about it. A recent unsubstantiated claim has been made regarding the continuous manufacture for a drug5 that has extremely limited demand and can only be economically produced using batch process. Such claims defy engineering and business logic.
It is ironic that many of the continuous manufacturing accepting naysayers have now joined in the chorus, singing its virtues as the new “to be and to do” technology. Some publications and conferences that dreaded the words continuous manufacturing have suddenly embraced it to impress everyone. Thus our new acronym “CM” is born. I am not sure if the economics and reality of the process is really understood. Process technology and economics need to be answered and addressed6 for the plants that can produce an API continuously or formulate it continuously.
As I suggested earlier that very few APIs—probably less than 10—can be produced using a continuous process. There are many drugs that can be formulated continuously but require justification and an absolute command of the process.
Fundamentals of chemistry, chemical engineering and process controls have to apply and work more than 100% for the success of continuous processes. Technologies—blending, controlled mass-feeders, etc.—have to be tested and precisely married to deliver formulated products that are “spot on” quality specs day in and day out. Feedback process controls that have been designed, developed and used for more than 60 years have to be tested for each product. Mid-course correction in blending and tableting operations impact product specs and performance and have to be precise and understood.
Up and down side of technologies
Again, for continuous processes to succeed there has to be complete and repeatable command of every process condition, unit operation, and operating parameter that influences product quality. If done so, in due time acronyms like PAT and QbD would disappear from pharma’s formulation vocabulary.
Most of the discussion related to pharmaceutical manufacturing centers around formulations. API manufacturing is ignored and I feel it is considered a necessary orphan that just happens to be an intruder in the landscape. We have to recognize that without an API we do not have a drug.
For a continuous formulation process supply of consistent quality raw materials to operate the process producing the same drug, about 7,000 hours per year is a must. If the operating equipment producing a single drug/dose is idle more than 40% of the 8,400 hours available per year, then the operation is similar to the current batch business model. Actually the investment could be considered a waste.
Any operation that is producing more than 60% of the global API need would have much better technology giving it a cost and quality advantage. In some cases, a continuous process could produce it. API consolidation would be necessary.
Since every kilo of API produces a million tablets of milligram doses each, generally formulation plants will have to operate more hours relative to the API plant. A properly and strategically designed continuous plant could fulfill the need and eliminate the need for many contract formulation plants producing the same drug. Basically, when all is said and done, efficient and properly designed continuous API and formulation plants will result in the consolidation of a significant number of operations.
Conclusion
My reasons and rationale for putting all of the above on paper is not no discredit or challenge anyone’s knowledge and desire to embrace the best available technologies that will enhance profits, improve revenues and make drugs affordable to billions. I just want to share my perspective of the up and downside of the technologies we can practice in pharmaceutical manufacturing. Investment justifications for technologies we use or will use are a must. Blind faith equals financial waste. Adoption of a technology that might be good for a certain product does not mean that it will be good across the landscape.
Continuous manufacturing does not fit every hand. It has to be custom fitted. It is not a fashion that is economical and suits everyone’s needs. Before we all start touting the values and benefits of continuous manufacturing, of which there are many, every pencil needs to be sharpened. Every “t” crossed and “i” dotted will show the value (e.g. high inventory turns with high asset utilization) but also show the downside and the challenges, especially for the batch formulation operations. There are bold opportunities ahead and if adopted will alter the current pharma manufacturing landscape. The faint hearted will have to consider how to manage and survive in this altered playing field.
References
- Process analytical technology, https://en.wikipedia.org/wiki/Process_analytical_technology Accessed March 6, 2017
- Malhotra, Girish: Quality By Aggravation or Quality By Desire? http://www.pharmpro.com/blog/2010/03/quality-aggravation-or-quality-desire Accessed March 7, 2017
- Malhotra, Girish: A Blueprint for Improved Pharma Competitiveness, Contract Pharma, September 1, 2014.
- Continuous production, https://en.wikipedia.org/wiki/Continuous_production, Accessed March 7, 2017
- Malhotra, Girish: Continuous Pharmaceutical Processes and Their Demands, Contract Pharma, April 5, 2016
- Malhotra, Girish: Manufacturing Processes Require Financial Justification, Contract Pharma, September 9, 2016
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.
