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All opinions are my own.

Thursday, March 21, 2024

Use of Tradition, Creativity, Imagination and Technology Innovation in Propofol Manufacturing

Title in itself can be questioned by some or many for any and every discussion. It should not be, if we look at everything that is manufactured. Everything starts from rudimentary paper concepts  with subsequent intervention of humans and science that makes the products and their manufacturing process elegant, useful and easy to use. It is well known that creativity and imagination when applied to any product and/or process leads to excellent results. Perspective presented is my own and there is no relationship or influence of any profit, nonprofit organization or regulatory body.

 

Methodologies used for process development and manufacture of fine/specialty chemicals which includes active pharmaceutical ingredients (API) are same. APIs are younger cousin of fine/specialty chemicals. However, they are treated differently even when exactly the same/similar chemicals, processes and equipment are used to produce each of the molecules. The only difference is API’s cure a disease whereas fine/specialty chemicals enhance lifestyle (1). It is true that APIs have to follow stricter regulations as they are used to cure diseases. Pseudo-assumption that APIs are nobler than their older cousin, fine/specialty chemicals, is unnecessary and very convoluted. 

 

If one traces a chemical molecule being developed in a laboratory equipment and has been synthesized It uses same/similar in every process development. Paper chemistries are tested and tweaked to create a process that the developer considers to be economic and optimum. Real test of this hypothesis comes when the process is commercialized.  

 

Every chemical entity for its production has a defined process and method. Even though I have reviewed and presented my perspective (1,2,3), it is never redundant to re-visit and share steps I would take to develop and commercialize a product. My team “THE VILLAGE” (1,2,3) will include a chemist, a chemical engineer, an accountant (can be a chemist and/or chemical engineer who is well versed in cost analysis), quality control, purchasing and manufacturing. Extent of their involvement will vary as the project progresses.

 

Every fine/specialty chemical plant that includes active pharmaceutical ingredient (API) should follow the outlined or equivalent path/s (1,2,3). There is value in this methodology or similar practices. They are documentation of reason and rationale for the process design and its basis. They assist in every regulatory filing and facilitates every trouble shooting and expansion if needed. 

 

Village (1, 2, 3) has to address each of the following items. If a village is not involved from inception, costs can be higher and commercialization can be delayed.


1.     Product volume per year

2.     Physical, chemical properties, mutual behavior and toxicity of raw materials, intermediates 

3.     Mass balance

4.     Process chemistry and manufacturing methods/procedures (unit processes)

5.     Process equipment and metallurgy (unit operations)

6.     Method/s used to feed the raw materials and transfer intermediate reaction products

7.     Raw material and Product specifications

8.     Effluent/waste treatment

 

Table 1: Information needed for an excellent chemical synthesis process

 

Collected information (1,2,3) Table 1 gives significant clues about the process. To every experienced chemists and chemical engineer it gives clues about how to finesse and capitalize on mutual behavior of chemicals. This information influences product cost and process economics. If the process involves multiple reaction steps and can be fitted in the existing equipment, it is very likely that the process will be inefficient and repeated analysis of process intermediates and the final product would be necessary, a characteristic of a classical batch process. Such processes for APIs would have low asset utilization (4).

 

If a product is a high volume product and the process involves multiple steps i.e. sequential processing steps without interruption, it can be conducive to a continuous process. Every village (1, 2, 3) team member has to be familiar with the development and commercialization process. Such processes are economic. However, generally this methodology has not been part of the API landscape. For a process to be a continuous process (5) product has to have sufficient volume (Kg/year) to operate 24 hours per day, seven days per week and about 50 weeks per year with some allocated downtime for maintenance. For such processes equipment design will be product specific.   

 

Based on my experiences any product that has multiple synthesis steps when fitted in the existing equipment  is generally a batch process. Fitting processes in existing equipment have inherent drawbacks of poor design and less than efficient asset utilization. Excess solvents, water or organic/s, are needed to assure proper processing. They have high emissions (6, 7). Along with low process productivity process yields are generally less than optimum. 

 

Continuous processes are not adopted by the brand pharma companies. Reason is simple. Speed to market. Once the product’s efficacy is recognized, it is submitted for regulatory approval. That is the key. Since the market size is not defined, batch process is the selected process. Any process changes require regulatory reapproval and that can be very expensive. In addition, village is not involved in their business model. This can delay the commercialization of process. For the generics many APIs of high volume can be produced using continuous process but will necessitate different business model. Only an outlier company will consider such options (1,2,3, 8)

 

Manufacture of Propofol: 

 

Five alternate refenced chemistries (9,10,11,12,13) for the manufacture of Propofol are presented. Items discussed in Table 1 have to be incorporated. Village team should review each of the experiments in the lab to get a feel for the process, flow of materials and mutual behavior of chemicals. This can unleash their creativity and imagination and would facilitate the scale up and commercialization of an excellent process. Raw materials should be of commercial grade quality and do not need to be pharmaceutical grade i.e. high purity. They are expensive and add unnecessary cost and may not be any different from the commercially available raw materials. Quality of the final product has to be the final driver. 

 

Raw materials for Propofol synthesis (9,10,11,12,13) Table 1 influence process design and selection. Chemistries described (9,10,11,12) are similar. In reference (13), the starting material is different. De-carboxylation step is executed differently. For process selection each of the outlined process chemistry needs a thorough review. 

Execution of laboratory processes in the plant will be very different from what is being discussed in these papers and patent. Again, each process has to reviewed carefully. Described chemistries (9, 10, 11, 12)  present an excellent opportunity for a continuous process (5). Purification or distillation of Propofol is based on chemical engineering distillation practices and there is no novelty. 

 

Items of Table 1 can be applied to select the best and the simplest process. Since 4-Hydroxybenzoic acid is solid at room temperature, its addition can be controlled if it is used as a melt or in a solvent that has high solubility. Scheme one (9)because of its simplicity could be the most likely candidate for a continuous process. 

Stoichiometry and process conditions can be precisely controlled and make an excellent case for a continuous process (1). Depending on the process selection (batch vs. continuous) design, feeding of aluminum chloride (2) has to carefully thought through. 

Yearly production volume is a very important criterion for selection of a batch or continuous process. Since propofol is a widely used for anesthesia its global use would be high. Sales of finished Propofol speculated by many, too many to cite. For Propofol as API no numbers were available. With consultation of Dr. Albinus D’Sa (16), it is estimated that between 250,000 to 300,000 MT per year would be needed to meet global needs. 

 

Since Propofol is a generic product only a new entrant in the business would use what has been described but the principles and methodology can be used by any fine/specialty and API business. 

 

 We have to remember that every multiple step chemical synthesis is an opportunity to simplify the process. This is easier said than done. Total knowledge and command of the chemicals used and produced in the process is a MUST. Knowledge of the unit operations (14) and chemical and physical properties (1, 2, 3) is essential. Application and inclusion of the knowledge simplifies the process and give command to produce quality product whether it is a batch (15) and/or a continuous process (6). A distinct advantage of a continuous process is that it can be ramped up to meet sudden surge in product demands. 

 

Some of the discussion above has been reviewed earlier (1, 2, 3, 8). Use and inclusion of parameters outlined in Table 1 allows proper process equipment (1) design and can reduce investment. Since Propofol is already commercial most likely not much will change unless an outlier company decides to enter the business. For any outlier it would be necessary to know the yearly demand for the Propofol API.


For process selection (batch vs. continuous) global how much active Propofol is produced is not available. Only number available is projected speculation of finished product. That does not give a reliable number. After consultation and discussion with Dr. Albinus D’Sa (16), different anesthesiologists, published information (17, 18) and world population (19) best number has been calculated, Table 3. Total Propofol active molecule needed is large enough to have an excellent continuous process. Continuous operations can be ramped to meet fluctuating active molecule need. 

Similar analysis can be done for many other products. Options exist for continuous processes for many other products exist and need a review along with business model change. They can be used to alleviate shortages. 

 

Girish Malhotra, PE

 

EPCOT International 

 

References:


1.     Malhotra, Girish:  Active Pharmaceutical Ingredient Manufacturing: Nondestructive Creation De Gruyter April 2022

2.     Malhotra, Girish: Chemical Process Simplification: Improving Productivity and Sustainability  John Wiley & Sons, February 2011 

3.     Malhotra, Girish: Chapter 4 “Simplified Process Development and Commercialization” in “ Quality by Design-Putting Theory into Practice” co-published by Parenteral Drug Association and DHI Publishing© February 2011

4.     Benchmarking Shows Need to Improve Uptime, Capacity Utilization, Pharma Manufacturing Sep 19, 2007

5.     Continuous Processing Accessed February 12, 2024

6.     Burke, J. What does net zero mean?, May 2, 2019 Accessed April 27, 2021

7.     Sheldon R.A. The E factor 25 years on: the rise of green chemistry and sustainability, Green Chemistry, 2017, 19, 18-43 Accessed February 17, 2021

8.     Profitability through Simplicity

9.     Pramanik  C. et. al. Organic Process Research Development, 2014, 18, 152-156

10.  Mougeot, R. et al Continuous Flow Synthesis of Propofol. Molecules 2021, 26, 7183

11.  Guilherme M. Martins et. al. Scaled up and telescoped synthesis of propofol under continuous-flow conditions Journal of Flow Chemistry (2022) 12:371–379 , 

12.  SCHNEIDER, Jean-Marie et.al. Process for producing Propofol WO/2023/111488  

13.  USP 11,767,281 B2

14.  Unit operations of Chemical Engineering, McCabe, W.L. Smith et. al McGraw Hills Inc. 1993, Accessed February 17, 2024

15.  Batch Production Wikipedia Accessed July 6, 2017

16.  D’Sa, Albinus Dsa Pharma Associates,

17.  Braun B: Miljöinformationen för propofol är framtagen av företaget Aspen Nordic för Diprivan 

18.  Sweden population https://www.worldometers.info/world-population/sweden-population/

19.  World population https://www.worldometers.info/world-population/














 















 

Friday, February 23, 2024

Manufacturing Technology Innovations in Pharmaceutical Manufacturing:

If we look at the history of disease curing products aka drugs, we will see that they started to appear about 80-90 years ago. Rapid discovery of disease curing value of existing and new disease curing chemicals and ease of their manufacture in the existing equipment being used to manufacture dyes and colorants led to an accelerated growth of the pharmaceutical industry (1). Discussion presented here is my own with the hope that any and all ambiguities I have will be clarified. Discussion is not influenced by any for profit, non-profit or regulatory body. 

 Pharmaceutical manufacturing technologies and methods: 

 

About 80-90 years ago chemical processing equipment was available and being designed for the dye and colorant industry. Many fundamentals of chemical engineering and unit operations (2,3,4,5) were explained and applied for the manufacture of various organic chemicals also called fine/specialty chemicals. They simplified manufacturing processes. Chemical engineering principles, manufacturing technologies and chemistry teachings of yester years are still the fundamental building block in every chemical manufacturing process. Active pharmaceutical ingredients (API) and their formulations are part of the same domain.  Some may disagree with this statement but one cannot change fundamentals as the methods are the same. Bio drugs are not part of the discussion. 

 

Competition and profitability has played a significant role in the development of the pharmaceutical industry. APIs, life span extenders, synthesized use same or similar equipment that was used in 1940-1960s. Except for normal enhancements/innovations with time, basic unit processes and operations have not changed. Fundamental processes and synthesis methods have not changed also. Execution methods might have changed. 

 

Fine specialty chemical companies, from (1940’s-’70s) who discovered disease curing molecules re-branded themselves as drug/pharmaceutical companies. They patented their molecules and formulations. This is very simple explanation of the landscape change. Except stricter regulatory requirements there in not much differences between fine/specialty and disease curing chemicals. Some may not agree but that is a historic reality.  

 

Due to extended time expended in discovery of disease curing molecule and regulatory approval companies have a limited patent life. To maximize profits, speed to the market is the utmost necessity. Ability and creativity of chemists and chemical engineers for use of existing equipment has been the operating mantra. Process inefficiency (low conversion) and equipment downtime (6) which can amount to as much as 50% of the available yearly equipment use time are accepted. All of these costs are passed on to the patient. 

 

Discussion here is focused on API manufacture. For formulation operating tactics, needs and philosophies are different and not part of the conversation. In the production of every product whether it is an organic additive chemical or a drug molecule annual volume of the product is important. They are based on economics and dictate manufacturing technology and methodology. No one is going to invest in any equipment and technology that is specifically designed for a product and is going to be used for a short time e.g. few weeks per year unless it is a monopoly case, patented product. Company find an alternate method/way to produce the product if any alternate equipment is/was available or modify the process to produce the product. This has been the operating philosophy in the pharma’s active ingredient (API) manufacture. As soon as the patent expires many may jump in with better manufacturing technologies. 


Still with opportunity to use better manufacturing technologies for API and their formulations innovation has stalled due to speed to market, profits and regulations. For innovation, there has to be grass root effort. Unfortunately brand companies do not have the time as their focus is speed to market and immediate profits. Generic companies have the opportunities but they have followed methods and practices of the brand companies and have not spent time to investigate/practice technologies that are better than practiced by the brand companies. My conjecture is that drug purchasing model used especially for USA drug distribution has prevented manufacturing technology innovation (7). If the generic companies could sell directly to US patient base, innovation in manufacturing technologies and methods (8) will change the landscape and shortages could be minimized and/or disappear (9)


On the API manufacturing and technology landscape few new terms have been recently introduced. I am told that they are the new technologies and simplify chemistry, process development and reduce commercialization time. These are:  


1.     Flow Chemistry

2.     Continuous manufacturing

3.     Process intensification


I do not find them anything close to new innovation but new names for well-known and practiced methods/technologies that have existed and practiced for the manufacture of chemicals for the last eighty years. I call these “fancy dance foot work” but the dance or the music has not changed. 


Flow Chemistry: I have asked for definition and clarification but have not been given a plausible answer. Folks who mention this on their curriculum vitae have not been able to explain and give definition of the term and/or an example and compare with traditional methods. Internet search suggests “Flow chemistry involves the use of channels or tubing to conduct a reaction in a continuous stream rather than a flask” (10, 11)


It is suggested that “Flow Chemistry simplifies chemistry and process development. I am not sure of this claim. I just wonder how solids would flow unless they are in liquid or solution state. Solids will have to be solubilized and that is no different from the current methods. In addition, based on the illustrated schematics it seems significant pre-engineering and investment would be need for the equipment needed. I wonder how versatile will be the applicability of the assembled equipment for different chemistries. Could they be used for other process developments? Would modifications be needed? I am not sure. 

Reviewing suggested process development methods based on use of flow chemistry (10, 11) they look to be expensive and cumbersome. This is based on the fact that information needed and used in traditional process development methods, knowledge of the physical properties of chemicals and their mutual behavior (1) would still be needed before “flow chemistry” based process contraptions described in (10, 11) can be assembled and used. A side by side economic analysis of the “flow chemistry” and traditional methods is necessary. My speculation is that the proposed methods will turn out to be financially expensive and time consuming. I hope use of term “Flow Chemistry” is not being used to impress others. 

 

Based on literature search and what I understand, incorporation of the proposed methods if possible, will be complex, expensive and time consuming. Results will be no better than what can be accomplished by current and proven methods. 

 

Based on my more than half a century of experiences in the chemical industry as a chemical engineer, generally there is methodology followed for development of chemical synthesis processes. Most of us are familiar with the methods. Reactants in appropriate solvent are added to a round bottom flask or similar equipment with its agitator and condenser and other necessary equipment. Reaction feasibility and safe operating conditions are defined. Chemist/chemical engineer generally  try different process conditions for process optimization. Next step is scale up and commercialization. 

 

Information i.e. physical, chemical properties, mutual behavior of chemicals used and produced, reaction kinetics i.e. fundamentals of chemical engineering (3, 4, 5) have to be collected by the village (1,13) and used for process development. My conjecture is that if all this is done, time needed for economic process technology development would be significantly reduced. Companies developing manufacturing technologies have to make process technology development a group activity (1,13).

 

My conjecture is that exploring what is called “flow chemistry” is an unnecessary stop i.e. prolonging process development and commercialization time. API developers/manufacturers need to think very hard on the value of proposed methods. There is an easy way to address and answer the question and it is “would the developer chemist/ chemical engineer invest their own money to develop the information that can be produced by simpler and quicker methods? 

 

We have to remember that majority of the APIs are produced using batch processes as they are fitted in the existing equipment. Information generated by “flow chemistry” methods might satisfy lab curiosity but may have minimal commercial value. Existing methods/practices can generate the same information faster. 

 

Continuous Manufacturing: In recent years “continuous processing” (14) is being touted as the way to produce APIs. No one has been able to give a satisfactory definition of “continuous processing”. When asked the definitions are confusing and they end up calling a batch process a continuous process. 

Following is my understanding of any continuous process. In every continuous chemical related process raw materials are introduced in appropriate equipment and using different unit processes and unit operations they are converted to the desired product. Each step has to be time independent. If there is fluid movement interruption, the process ceases to be a continuous process. We cannot modify established principles to suit our fancy. This also applies to drug formulations.   


Every continuous process is product specific and if another product process does not use the same unit operations, it cannot be produced year round in the same equipment. No one is going to invest in product specific equipment that is not operating year round. It is not going to have the desired financial return. 


Certain existing API products that are produced by batch process can be produced using continuous processes but for them business and operating model would have to change (1). It is my perspective that under pharma’s current sales and distribution model APIs do not have the volume to be produced continuously. An outlier producer and a different sales and distribution model (8) will be needed for continuous API production. Yes, formulations can be operated continuously but can be a challenge.  


Process intensification: This terminology is a new one for methods that have existed since the advent of chemical manufacturing and been used at least since 1960s for the manufacture of fine/specialty chemicals. If use of venturi flow, plate and frame heat exchangers, static mixers, eductors and restricted spaces to improve and enhance mixing of liquids to improve reaction chemistry is considered process intensification then this is not a new technology. It is an old art. Creativity and imagination help. Equipment economic analysis is a must.  

 

I hope we have not forgotten fundamentals of chemical engineering. Renaming existing methods that have been and are commercially used as new technologies is not ethical. Microreactors are capital intensive and have limited use. Similar results can be achieved by using existing alternate equipment.  

 

Since I am still learning, any verifiable examples are welcome. Intent here is not to challenge anyone’s knowledge or creativity but learn and augment knowledge. I have been able to use the wisdom taught by wizards of chemical engineering (3,4,5). I believe flow chemistry and process intensification are application of principles of chemical engineering that have existed and used but are worded differently to attract attention to be new. 

 

All said and done we have to remember what works in the lab does not necessarily work in the plant. Everything has to be proven before it becomes commercial. I welcome any and every meaningful discussion. API manufacturing platforms, that exist and have been continually improved, need to be judiciously considered and applied (2, 3, 4, 5). New names for the existing methods are not going to win any laurels. 

 

Judicious involvement of village (1) is needed from product inception state. This concept of technology development unlike science, is a group activity (13). Some of the processes that are the result of such village/group activity are reviewed (1). Unless there is change in how the process and technology is developed and used to commercialize better API manufacturing technologies, not much will change. Calling established processes and/or methods by new names is not new technology and is not going to reduce process development and commercialization time.

 

 

Girish Malhotra, PE

 

EPCOT International

 

1.     Malhotra, Girish: Active Pharmaceutical Manufacturing: Nondestructive Creation De Gruyter April 2022 Accessed February 17, 2024

2.     Unit Operations Accessed February 17, 2024 

3.     Unit operations of Chemical Engineering, McCabe, W.L. Smith et. al McGraw Hills Inc. 1993, Accessed February 17, 2024

4.     Walker William H. et al Principles of Chemical Engineering, McGraw Hill Book Co. Inc. 1933

5.     Levenspiel, O: Chemical Reaction Engineering, John Wiley & Sons 1999

6.     OEE Benefits for Pharmaceutical, BioTech and Medical Device Manufacturers in Life Sciences, Pharmaceutical Technology August 27, 2015

7.     Malhotra, Girish: USA’s Annual Ritual of Drug Sourcing/pricing and Shortages, Profitability through Simplicity, November 25, 2023 Accessed February 15, 2024 

8.     Malhotra, Girish: Simplified Process Development and Manufacturing of Fine/Specialty Chemicals & Active Pharmaceutical Ingredients, Profitability through Simplicity, Feb 14, 2023 

9.     Malhotra, Girish: Roadmap to Reduce Drug Shortages and Bring Pharma Manufacturing Home (US) Profitability through Simplicity, October 30, 2023 Accessed February 17, 2024

10.  Plutschack M. B. et al: The Hitchhiker’s Guide to Flow Chemistry Chemical Reviews, 2017, 11718, 11796-11893 Accessed February 17, 2024

11.  Guidi, M.  et al How to approach flow chemistry Chem. Soc. Rev.2020,498910-8932, Accessed February 17, 2024

12.  Malhotra, Girish: Chemicals tell us how to exploit their behavior for better processes. Clues are ignored. Should we? Profitability through Simplicity, June 20, 2023 Accessed February 17, 2024

13.  Kalam, APJ Abdul, Wings of Fire: An Autobiography of APJ Abdul Kalam, Sangam Books Ltd, 1999 Accessed January 31, 2024

14.  Continuous Processing   Accessed February 12, 2024