About five years ago FDA issued its “PAT Guidance for Industry” (September 2004). FDA’s intent by issuing the guidelines is to encourage the Pharmaceutical Industry to improve and innovate its manufacturing practices so that they produce quality product the first time and all the time. Manufacturing innovation will be the lifeline for the Pharmaceuticals as their business model changes.
Regulatory bodies want the companies to move away from achieving quality through the current practice of “after the fact repeated analysis”. Achieving product quality “the first time” and all the time is the goal. This is not a difficult expectation.
The guideline is suggesting the industry of how and what needs to be done and the methodology for improving the processes. However, innovation has to come from within the industry rather than thrust upon them. The guidance is very legalese and can be interpreted in many different ways. As written it eludes more to drug formulation than to Active Pharmaceutical Ingredient (API) manufacture. However, the rules of the game for API and drug formulation are same as quality is the ultimate goal.
If we clear the forest and the legal jargon, FDA is saying “understand how the chemicals react, interact and behave with each other and have a process that if operated at the desired process conditions should deliver quality product the “first time” and all the time [basic tenants of chemical engineering, chemistry curriculum and process development]”. Anything short will not deliver first time quality product.
In product and process development, we need to understand the chemicals, their interaction, establish specifications and use different analytical technologies to ensure that the developed process will deliver the expected product. If one is expecting that the process analytical technologies will fix a bad process, then that would be a gross error and expectation. Analytical technologies tell us the result rather than the path to the result.
Good manufacturing practices and continuous improvement is a must for every manufacturing. PAT guidance suggests that the pharmaceutical industry should have discussion and approval from FDA on their existing process improvement plans. This is adding costs. The benefits of process improvement can be quantified but since the re-approval costs are not known, my conjecture is that the industry would not opt for any process improvement for their existing products as the costs could exceed the benefits. Estimated savings due to process innovations for the pharmaceutical companies are in the $100 to $200 billion dollars range. I hope this is good incentive to innovate.
Pharmaceuticals companies due to first to market pressures and following regulatory directives and guidelines are not able to apply good chemistry and engineering principles to have an efficient process that produces quality product. The current state of pharmaceutical manufacture is manifestation of our methods. If we are expecting it to change pharmaceutical companies have to take the lead. Innovation can happen for the products that will become generic in the coming years and for the new molecules that will be commercialized.
Development of innovative processes has to start during the process conceptualization and development. Even then it would have to be an effort as old methods and thinking would have to be discarded, which is not easy. The regulatory bodies will have to be flexible and encourage innovation. PAT guidelines and other guidelines are encouraging innovation but have too many constraints. I strongly believe that innovation can reduce regulation.
Girish Malhotra, PE
President
EPCOT International
Thursday, October 8, 2009
Friday, September 25, 2009
Fine Chemicals: Quality Manufacturing and Technology Innovation in Pharmaceuticals
A recent survey “Pharmaceutical Process Control: Is the Great Divide Growing?” makes one think and ponder about the direction of manufacturing technologies and process development methods in the changing pharmaceutical business model.
I found some of the answers to be conflicting. The problems of technology inefficiencies should go away are the expectation. However, costs and how to go about comes in the way. Survey suggests that PAT and QBD could be mutually exclusivity, this was a surprise and as they cannot be.
For a chemical process to produce quality product complete understanding and incorporation of the physical properties of chemicals, their reaction chemistry and interaction is necessary. Understanding facilitates development of an excellent process. These are the fundamental elements of QBD and PAT.
Survey raises the following questions.
1. Do the survey answers give the direction of the company as a whole or only the thinking of the participating staff? Is the staff opinion in sync with what the management wants?
2. What is management thinking with respect to manufacturing and process technologies?
3. Are the survey questions such that by answering “yes” to one part of the survey could result in an automatic “no” for the other part of the survey i.e. consistency or lack of it?
My focus is on having the best Process Development and Manufacturing technologies so that we can have a process that is safe, environmentally sustainable and produces quality product first time and all the time without repeated analysis.
If we understand the fundamental elements, our creativity and imagineering should result in “state of the art” processes that will produce a quality product. Proper process controls are derived from such knowledge.
Unless we understand the fundamental elements, after the fact improvement effort (Lean, Six Sigma etc.) would not result in an optimum process. Actually such an effort can be expensive. Incomplete understanding will result in less than an optimum process. It will be an expensive investment as is the case in Pharmaceutical Manufacturing.
Knowledge of elements will facilitate incorporation and adoption of state of the art and new technologies. Microreactors are the new “to be discussed” technology after the pharma acronyms. They are being touted as the next best thing after sliced bread.
For the last ten plus years “micro-reactors” have been a laboratory curiosity. Microreactors are simplistically a reaction space that act as an efficient heat exchange device also. If used properly can lead to an “efficient, green and sustainable” process. They are a modified/enhanced nano-version of plate and frame heat exchangers, which have been commercial for 40+ years. Such exchangers have been primarily used as heat exchangers rather than a combination reaction and heat transfer space. They perform extremely well in their dual role. These and similar technologies have to be understood and their value capitalized. Such reactors have a place in the pharmaceuticals (specialty chemicals) and fine chemical world.
Use of innovative technologies and improvement of manufacturing practices is only possible if we understand the fundamentals and apply principles of chemical engineering for an optimum process. Effort is not expensive and once incorporated, we would see very positive results.
Girish MALHOTRA, PE
President
EPCOT International
I found some of the answers to be conflicting. The problems of technology inefficiencies should go away are the expectation. However, costs and how to go about comes in the way. Survey suggests that PAT and QBD could be mutually exclusivity, this was a surprise and as they cannot be.
For a chemical process to produce quality product complete understanding and incorporation of the physical properties of chemicals, their reaction chemistry and interaction is necessary. Understanding facilitates development of an excellent process. These are the fundamental elements of QBD and PAT.
Survey raises the following questions.
1. Do the survey answers give the direction of the company as a whole or only the thinking of the participating staff? Is the staff opinion in sync with what the management wants?
2. What is management thinking with respect to manufacturing and process technologies?
3. Are the survey questions such that by answering “yes” to one part of the survey could result in an automatic “no” for the other part of the survey i.e. consistency or lack of it?
My focus is on having the best Process Development and Manufacturing technologies so that we can have a process that is safe, environmentally sustainable and produces quality product first time and all the time without repeated analysis.
If we understand the fundamental elements, our creativity and imagineering should result in “state of the art” processes that will produce a quality product. Proper process controls are derived from such knowledge.
Unless we understand the fundamental elements, after the fact improvement effort (Lean, Six Sigma etc.) would not result in an optimum process. Actually such an effort can be expensive. Incomplete understanding will result in less than an optimum process. It will be an expensive investment as is the case in Pharmaceutical Manufacturing.
Knowledge of elements will facilitate incorporation and adoption of state of the art and new technologies. Microreactors are the new “to be discussed” technology after the pharma acronyms. They are being touted as the next best thing after sliced bread.
For the last ten plus years “micro-reactors” have been a laboratory curiosity. Microreactors are simplistically a reaction space that act as an efficient heat exchange device also. If used properly can lead to an “efficient, green and sustainable” process. They are a modified/enhanced nano-version of plate and frame heat exchangers, which have been commercial for 40+ years. Such exchangers have been primarily used as heat exchangers rather than a combination reaction and heat transfer space. They perform extremely well in their dual role. These and similar technologies have to be understood and their value capitalized. Such reactors have a place in the pharmaceuticals (specialty chemicals) and fine chemical world.
Use of innovative technologies and improvement of manufacturing practices is only possible if we understand the fundamentals and apply principles of chemical engineering for an optimum process. Effort is not expensive and once incorporated, we would see very positive results.
Girish MALHOTRA, PE
President
EPCOT International
Friday, August 21, 2009
A Pharmaceutical Challenge for Technocrats
Pharmaceuticals have their own unique technology and pricing positions compared with the other chemical products. Can we introduce innovative development and manufacturing technologies for the pharmaceuticals sector? The answer in unequivocal ‘yes!’ We just need to understand the roadblocks and overcome them.
Since we want to live forever, we are willing to pay the demanded price for a drug. Our willingness to pay for long life along with the monopoly during the life of the patent has been the primary driver for setting drug pricing. Drug prices are set at the highest level the market will bear. Once the patent expires, brand companies move on to invent new drugs.
The above two factors ensure the desired profit margins for the pharmaceutical companies. Any costs due to regulatory mandate are passed on to the consumer. Thus, the need for product, process development and manufacturing technology innovation has been minimal. Inefficiencies are an accepted part of doing business. Generics have followed ethical (brand) companies in their modus operandi.
Regulatory bodies have cajoled pharmaceutical companies toward innovation by creating PAT, CMC, QBD and other TLAs. However, these cannot be forced or mandated unless some other event takes place, which will have a financial return. [We are familiar with the phrase “you can lead the horse to water but cannot make it drink.”]
There has to be a solution for this dilemma. Only an “economic incentive” will result in innovation.
Latent blame for the lack of innovation is placed on regulatory agencies. This is unjust. The repeatability of quality at the active pharma ingredients (API) and the final formulated drug stages is mandated- as it should be. However, the “path to quality” should not be mandated. Companies should be held responsible for “quality failure”. Penalty for quality failure has to be severe. Companies should have the freedom to choose the “path to quality” as it is the road to innovation and creativity.
Providing manufacturers with the freedom to choose their “path to quality” is the equivalent of stopping the sampling of intermediates” for quality. This will force everyone to “drink the water”. Companies will save significant money, which will be additional incentive for pharmaceutical development and manufacturing technology innovation.
Stopping intermediate sampling could be encouraged and even mandated. It will happen only if we understand “everything about the raw materials and intermediates but were afraid to ask.” I am quite confident that based on the education and training that chemical engineers and chemists receive they can become the proponents of “stopping the sampling of intermediates.” With their backing we will arrive at the destination where the regulators want us to go. Technology innovation is not hard and for the technocrats it is the most exhilarating experience.
We need to keep API and drug formulation as separate processes and that will simplify innovation. In general, many articles discuss pharmaceutical process improvements. These do not include API manufacturing process improvements but only refer to formulation process improvements. McKinsey in a recent report suggests that the pharmaceutical companies have an opportunity that exceeds about $65 billion through productivity improvements in the drug formulation area. Based on my review of the API segment, I believe that the opportunity in the API sector based on yield, technology
improvements and conservation far exceeds $65 billion.
The question is: “Are the chemists and chemical engineers ready and willing to take the challenge?” I know the answer and it is “Yes we can”. If we do, many of the TLAs would become irrelevant.
Girish MALHOTRA, PE
President
Since we want to live forever, we are willing to pay the demanded price for a drug. Our willingness to pay for long life along with the monopoly during the life of the patent has been the primary driver for setting drug pricing. Drug prices are set at the highest level the market will bear. Once the patent expires, brand companies move on to invent new drugs.
The above two factors ensure the desired profit margins for the pharmaceutical companies. Any costs due to regulatory mandate are passed on to the consumer. Thus, the need for product, process development and manufacturing technology innovation has been minimal. Inefficiencies are an accepted part of doing business. Generics have followed ethical (brand) companies in their modus operandi.
Regulatory bodies have cajoled pharmaceutical companies toward innovation by creating PAT, CMC, QBD and other TLAs. However, these cannot be forced or mandated unless some other event takes place, which will have a financial return. [We are familiar with the phrase “you can lead the horse to water but cannot make it drink.”]
There has to be a solution for this dilemma. Only an “economic incentive” will result in innovation.
Latent blame for the lack of innovation is placed on regulatory agencies. This is unjust. The repeatability of quality at the active pharma ingredients (API) and the final formulated drug stages is mandated- as it should be. However, the “path to quality” should not be mandated. Companies should be held responsible for “quality failure”. Penalty for quality failure has to be severe. Companies should have the freedom to choose the “path to quality” as it is the road to innovation and creativity.
Providing manufacturers with the freedom to choose their “path to quality” is the equivalent of stopping the sampling of intermediates” for quality. This will force everyone to “drink the water”. Companies will save significant money, which will be additional incentive for pharmaceutical development and manufacturing technology innovation.
Stopping intermediate sampling could be encouraged and even mandated. It will happen only if we understand “everything about the raw materials and intermediates but were afraid to ask.” I am quite confident that based on the education and training that chemical engineers and chemists receive they can become the proponents of “stopping the sampling of intermediates.” With their backing we will arrive at the destination where the regulators want us to go. Technology innovation is not hard and for the technocrats it is the most exhilarating experience.
We need to keep API and drug formulation as separate processes and that will simplify innovation. In general, many articles discuss pharmaceutical process improvements. These do not include API manufacturing process improvements but only refer to formulation process improvements. McKinsey in a recent report suggests that the pharmaceutical companies have an opportunity that exceeds about $65 billion through productivity improvements in the drug formulation area. Based on my review of the API segment, I believe that the opportunity in the API sector based on yield, technology
improvements and conservation far exceeds $65 billion.
The question is: “Are the chemists and chemical engineers ready and willing to take the challenge?” I know the answer and it is “Yes we can”. If we do, many of the TLAs would become irrelevant.
Girish MALHOTRA, PE
President
Wednesday, August 5, 2009
Chemical Engineering: Understanding the Curriculum for Quality Manufacturing
Chemical Engineers during their training are taught that they will commercialize and/or operate a process that will produce consistent quality product all the time (without re-work) using a safe, sustainable and an economic process.
To achieve these objectives, we review topics that teach us the understanding of the physical properties of material (raw material, intermediate, by-product and the product) involved in the process. This allows us to understand their interaction in a reactive and/or a blending process. Chem. E. uses this information to commercialize a robust process.
If we have mastered the properties and the interaction of chemicals involved, we should be able to define the operating conditions of a process having the highest yield with above defined process characteristics. We are also taught various unit operations that we can use as is, modify and/or manipulate to produce a quality product all the time. If we are not able to achieve the objective of producing quality product using a safe and sustainable process, the first time and all the time, we have to improve our understanding so that we can have the correct process.
If I translate the Chem. E. training fundamentals to acronyms, we are taught to develop and commercialize a QUALITY BY DESIGN (QBD) process. This is our “hippocratic oath”. Anything short of this objective suggests that we need to improve.
Regulatory bodies have introduced few other acronyms in the pharmaceutical manufacturing. They are fine to have but what they mean and tell us is not totally understood. Interpretations of these vary and introduce variability. My question is: are we trying to have the best pharmaceutical manufacturing technology or are we trying to conform to the current fashion crowd?
My interpretation of QBA, CQA, CMC, DS, and PAT is as follows. If my understanding is not what the “guru’s” expect it to be, then please help with the correct interpretation.
• CQA [critical quality attributes]: We need to understand the physical properties of the materials (raw material, intermediate, by-product and the final product) and how they interact with each other.
• DS [design space]: Definition of the process operating parameters that have been identified by the developers, which if followed will produce quality product all the time.
• CMC [chemistry, manufacturing and controls]: Reaction mechanism, kinetics and process controls that is understood and followed will allow production of quality product.
• PAT [process analytical technologies]: This acronym is the least understood. It is believed that by having PAT, all of the process ills will go away. That is far from the truth. Analytical instruments will let the manufacturing and quality people know that the process has erred. However, it will not correct the problem and give a solution to the problem. Only people who are familiar with the characteristics of the materials and chemistry can correct the process. Analytical instruments are an indicator and not the corrector. There is difference between process control technologies and process analytical technologies.
• QBA [quality by analysis]: It suggests that we have a problem and we do not meet quality. We have to go back and fix the problem so that we can produce the desired quality.
To summarize the above mentioned acronyms are the fundamentals of chemical engineering curriculum. If we understand pieces parts of the curriculum, then we should have a QBD process. Question then arises why it is so hard to implement the fundamentals of chemical engineering in the manufacture of a pharmaceutical (API or a blend of API and excipients) or did I miss something.
Girish Malhotra, PE
President
To achieve these objectives, we review topics that teach us the understanding of the physical properties of material (raw material, intermediate, by-product and the product) involved in the process. This allows us to understand their interaction in a reactive and/or a blending process. Chem. E. uses this information to commercialize a robust process.
If we have mastered the properties and the interaction of chemicals involved, we should be able to define the operating conditions of a process having the highest yield with above defined process characteristics. We are also taught various unit operations that we can use as is, modify and/or manipulate to produce a quality product all the time. If we are not able to achieve the objective of producing quality product using a safe and sustainable process, the first time and all the time, we have to improve our understanding so that we can have the correct process.
If I translate the Chem. E. training fundamentals to acronyms, we are taught to develop and commercialize a QUALITY BY DESIGN (QBD) process. This is our “hippocratic oath”. Anything short of this objective suggests that we need to improve.
Regulatory bodies have introduced few other acronyms in the pharmaceutical manufacturing. They are fine to have but what they mean and tell us is not totally understood. Interpretations of these vary and introduce variability. My question is: are we trying to have the best pharmaceutical manufacturing technology or are we trying to conform to the current fashion crowd?
My interpretation of QBA, CQA, CMC, DS, and PAT is as follows. If my understanding is not what the “guru’s” expect it to be, then please help with the correct interpretation.
• CQA [critical quality attributes]: We need to understand the physical properties of the materials (raw material, intermediate, by-product and the final product) and how they interact with each other.
• DS [design space]: Definition of the process operating parameters that have been identified by the developers, which if followed will produce quality product all the time.
• CMC [chemistry, manufacturing and controls]: Reaction mechanism, kinetics and process controls that is understood and followed will allow production of quality product.
• PAT [process analytical technologies]: This acronym is the least understood. It is believed that by having PAT, all of the process ills will go away. That is far from the truth. Analytical instruments will let the manufacturing and quality people know that the process has erred. However, it will not correct the problem and give a solution to the problem. Only people who are familiar with the characteristics of the materials and chemistry can correct the process. Analytical instruments are an indicator and not the corrector. There is difference between process control technologies and process analytical technologies.
• QBA [quality by analysis]: It suggests that we have a problem and we do not meet quality. We have to go back and fix the problem so that we can produce the desired quality.
To summarize the above mentioned acronyms are the fundamentals of chemical engineering curriculum. If we understand pieces parts of the curriculum, then we should have a QBD process. Question then arises why it is so hard to implement the fundamentals of chemical engineering in the manufacture of a pharmaceutical (API or a blend of API and excipients) or did I miss something.
Girish Malhotra, PE
President
Tuesday, August 4, 2009
Climate Change and its impact on Industrial Production
Climate change is a new challenge and a major discussion point between the developed and the developing countries. Some sort of emission limits will be placed as we move forward. There is lot of posturing and both sides are making point and counterpoint.
Developed countries did not have emission restrictions during their growth. With the current demand to curb emissions, some curbs will be negotiated. Developed and developing countries are afraid of the curtailment of their industrial machine. In order to retain their industrial complex developed countries will exert pressure. However, the developing countries especially India and China are not going to readily agree to any curbs. In Secretary Clinton’s recent trip India Rejected U.S. Proposal of Carbon Limits.
A recent article India and Climate Change takes India as example and excludes China, though both present similar challenges for the developed countries.
This article states “If (the) developed nations are held responsible for emissions that they historically contributed, oblivious to their impact on climate change, why shouldn't (the) developing nations take responsibility for producing generations of people who will generate emissions into the future?” Is it an indirect admission that the developed countries are afraid of the curbing their economic growth and are afraid of the growth of the developing countries? It seems to suggest that since the developed countries control their population, they can keep emitting at the current per capita rate. Is it also suggesting that the living standards of the developed countries should stay high and of the developing countries should not? If this is the latent intent, it is not going to sit well with the developing countries.
Are we saying “Maslow’s hierarchy of needs” only applicable to the developed countries? Developed countries have had the developing countries as their market, but now they challenging us on our turf, we are not willing to accept the challenge. The game has changed and we will have to play with the new rules. Their development and negotiation is going to be a challenge.
Recently International Council of Chemical Associations engaged McKinsey & Co. to suggest steps the chemical industry needs to take to curb emissions and still innovate. This study excludes chemicals that improve the living standards (including pharmaceuticals) and assumes gross savings from such chemicals to be zero.
I have concerns about this exclusion as we are excluding an important segment (pharmaceuticals about $800 billion revenue out of $3 trillion dollars per year) that has a large carbon imprint. Pharmaceuticals (API and formulated products) present an opportunity to reduce their imprint. There is an opportunity to improve their manufacturing inefficiencies (low yield) and reduce their solvent use, there by achieving an offsetting positive impact. Technology improvement will also reduce healthcare costs. An effort is needed in earnest.
Development and global sharing of the low carbon emission technologies might be the answer. Other choice for the companies in the developed countries is to move their factories to the developing countries. Thus they would not have to implement tougher emission standards. This is not a viable option.
In the last 15-20 years countries have become dependent on each other. What was environmentally acceptable yesterday will not be acceptable tomorrow. Since the global warming will affect us all, we will have to compromise and live with the new rules whatever they might be.
Girish Malhotra, PE
President
Developed countries did not have emission restrictions during their growth. With the current demand to curb emissions, some curbs will be negotiated. Developed and developing countries are afraid of the curtailment of their industrial machine. In order to retain their industrial complex developed countries will exert pressure. However, the developing countries especially India and China are not going to readily agree to any curbs. In Secretary Clinton’s recent trip India Rejected U.S. Proposal of Carbon Limits.
A recent article India and Climate Change takes India as example and excludes China, though both present similar challenges for the developed countries.
This article states “If (the) developed nations are held responsible for emissions that they historically contributed, oblivious to their impact on climate change, why shouldn't (the) developing nations take responsibility for producing generations of people who will generate emissions into the future?” Is it an indirect admission that the developed countries are afraid of the curbing their economic growth and are afraid of the growth of the developing countries? It seems to suggest that since the developed countries control their population, they can keep emitting at the current per capita rate. Is it also suggesting that the living standards of the developed countries should stay high and of the developing countries should not? If this is the latent intent, it is not going to sit well with the developing countries.
Girish Malhotra, PE
President
Wednesday, July 8, 2009
Recycling Coatings: An Environmental and Business Opportunity
In today’s environmental concerns and how to reduce green house gases (GHG)/carbon imprint, an opportunity exists in the coating business areas and that can appease many. This is through recycling of coatings.
Recycling of coatings is a possibility and a challenge. The challenge comes from the perspective of the formulators and the raw material suppliers. Raw materials deliver the desired coating performance. If the raw materials can be used interchangeably to deliver the required performance, we can have the makings of easier recycling and better manufacturing (batch à continuous) technologies. Certain scenarios exist.
Kelly Moore, a
Over the last many years, different methods and applications of surplus coating have been considered with sporadic success. Sustained success is needed to reduce environmental impact of the coatings.
If the government mandates coating recycling through EPA regulations, it would be called meddling in the business. However, the government can assist by creating an incentive program for the companies who recycle. This could be through VOC credits. This presents the best opportunity and any company’s effort in recycling should be awarded.
A joint effort will be needed to establish such VOC credit program. Companies should decide how they develop and incorporate the recycled material in their products. Companies have the knowledge base and the creativity to develop coatings that can have significant recycled material as a part of their formulation. Strategic and interchangeable use of different raw materials is the key for recycling. This would be a win-win.
Friday, June 12, 2009
Pharmaceuticals: What is Holding Back Quality By Design?
We come across many TLAs and their number is increasing. What is a TLA? It stands for “three letter acronym”.
In the regulatory world, TLAs keep us on our toes. In the pharmaceutical world two TLAs are in vogue. They are QBA and QBD. Everyone associated with the manufacture of pharmaceuticals is familiar with these acronyms. But just to re-iterate, QBA is product “quality by analysis” and QBD is “quality by design”. QBA is the current tradition of the pharmaceutical manufacturing processes whereas QBD presents what the technology should be or the future.
Level of going on discussion is suggestive of that there is a significant hesitation to improve technology. One has to ask the question, why it is so difficult to move from “A” to “D” and I am sure many have. There has to be a monumental hurdle/roadblock for the pharmaceuticals to move from QBA to QBD.
I do not think there are any hurdles. We are just up against tradition. Since the traditions are entrenched in pharmaceuticals, we have accepted the current manufacturing practices. They have not been challenged. We are also afraid of the “Regulatory Gods”. Move from QBA to QBD is very simple and the roadblock is staring at us. However, it has not been obvious to us. I define the hurdle/roadblock for the move from “A” to “D” to be “the isolation of intermediates of the reaction or the formulation steps”. The mantra for QBD is “stopping isolation of intermediates”.
If we isolate a reaction product after every reaction step or a mix after every formulation step to test the quality and the conversion yield, we are acknowledging that we do not have a complete understanding, control of the process step and its mechanism. If we did have the understanding, we would not be isolating the reaction step and/or blend intermediate and testing them for their quality.
Specialty/Fine chemical industry by and large has a complete understanding and control of the processes. It does not necessitate isolation of the intermediates, as the quality is designed in the products. If we can achieve the same level of proficiency for the pharmaceuticals, we would move from quality by “A” [analysis] to quality by “D” [design].
In the pharmaceutical industry move from “A” → “D”, will be a major accomplishment in simplifying the manufacturing technologies and processes. It will not only improve process efficiencies and but also reduce the carbon footprint of the fine, specialty chemicals and the pharmaceutical manufacturing processes. It will reduce the cycle time for many batch processes and could nudge quite a few products to be manufactured by continuous processes.
Jumping the “A” to “D” hurdle is simple and easy. We just have to set our heart and mind to it. If it happens, my conjecture is the even the “Regulatory Gods” will celebrate.
Girish MALHOTRA, PE
President
EPCOT International
In the regulatory world, TLAs keep us on our toes. In the pharmaceutical world two TLAs are in vogue. They are QBA and QBD. Everyone associated with the manufacture of pharmaceuticals is familiar with these acronyms. But just to re-iterate, QBA is product “quality by analysis” and QBD is “quality by design”. QBA is the current tradition of the pharmaceutical manufacturing processes whereas QBD presents what the technology should be or the future.
Level of going on discussion is suggestive of that there is a significant hesitation to improve technology. One has to ask the question, why it is so difficult to move from “A” to “D” and I am sure many have. There has to be a monumental hurdle/roadblock for the pharmaceuticals to move from QBA to QBD.
I do not think there are any hurdles. We are just up against tradition. Since the traditions are entrenched in pharmaceuticals, we have accepted the current manufacturing practices. They have not been challenged. We are also afraid of the “Regulatory Gods”. Move from QBA to QBD is very simple and the roadblock is staring at us. However, it has not been obvious to us. I define the hurdle/roadblock for the move from “A” to “D” to be “the isolation of intermediates of the reaction or the formulation steps”. The mantra for QBD is “stopping isolation of intermediates”.
If we isolate a reaction product after every reaction step or a mix after every formulation step to test the quality and the conversion yield, we are acknowledging that we do not have a complete understanding, control of the process step and its mechanism. If we did have the understanding, we would not be isolating the reaction step and/or blend intermediate and testing them for their quality.
Specialty/Fine chemical industry by and large has a complete understanding and control of the processes. It does not necessitate isolation of the intermediates, as the quality is designed in the products. If we can achieve the same level of proficiency for the pharmaceuticals, we would move from quality by “A” [analysis] to quality by “D” [design].
In the pharmaceutical industry move from “A” → “D”, will be a major accomplishment in simplifying the manufacturing technologies and processes. It will not only improve process efficiencies and but also reduce the carbon footprint of the fine, specialty chemicals and the pharmaceutical manufacturing processes. It will reduce the cycle time for many batch processes and could nudge quite a few products to be manufactured by continuous processes.
Jumping the “A” to “D” hurdle is simple and easy. We just have to set our heart and mind to it. If it happens, my conjecture is the even the “Regulatory Gods” will celebrate.
Girish MALHOTRA, PE
President
EPCOT International
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