USP 11,267,798 B2: Manufacture of Piperine (1) An Excellent Teaching Tool

US patents that relate to fine/specialty chemicals are an excellent platform where their synthesis details are shared. Their manufacturing methods and details are left to the imagination of chemists and chemical engineers who take the synthesis route using unit processes ⁽²⁾ and appropriate unit operations ^(3,4) from the lab to the manufacturing floor. This tradition has been ingrained for the manufacture of fine/specialty chemicals that are used to enhance lifestyle as well as the chemicals that extend life. These are called active pharmaceutical ingredients (API) which are formulated to appropriate dispensable dose. However, there is a significant difference about the quality rigor each product has to follow. 

Fine/specialty chemicals that enhance life style have to meet their quality standards. API manufacturing methods have to meet stringent quality standards that are approved by regulatory bodies. This is necessary as they are used to cure diseases. Altering their manufacturing process can require companies to prove product efficacy and that can be an expensive time and money process. As a result API manufacturing process improvements are stalled and or even might not happen. How the API manufacturing processes are scaled up depends on individual company. Most of the API manufacturing patents detail the synthesis route and share clues and if capitalized on can lead to a very economic and environmentally friendly process that has low emissions ^{(5, 6)}.

Reviewing in-process patent filings and granted patents teach ways to review/learn chemical process synthesis and their manufacturing practices ⁽⁷⁾. 
 
The exercise here is not questioning the knowledge and skills of the people and/or the reaction scheme/process but how the information can be used to create simpler processes. Questioning and exploring what we do in the laboratory is and has been an excellent learning and gratifying process simplification tool, at least for me. I am sure others have similar experiences and come up with better and easier ways to simplify chemical synthesis and manufacturing. 
 
Generally majority of the chemical synthesis processes are fitted in the existing equipment. This is due to speed to market especially after API regulatory approval. Chemistries outlined in the patents give us the reaction mechanism for every reactive process. We can capitalize on that knowledge to commercialize using most appropriate unit operations ^(3,4) an economic and environmentally friendly process ^{(5, 6)} and move away from the traditions of the last SIXTY PLUS years. Modular plants or equipment of the size used in pilot plants might be the answer as only select number of APIs have the volume to have dedicated plants. This requires re-evaluation of fine/specialty chemical and API business model. Due to profitability and constantly changing API landscape and regulatory hurdles only an outlier company would be willing to step up to the challenge. Perspective presented is my own and not influenced by any for profit and/or nonprofit organization. 
 
Every reaction chemistry and synthesis process tells us how the product can be produced. Laboratory is its proving ground. Synthesis is demonstrated in the laboratory and commercialized by generally fitting it in the available existing equipment. This entails using excessive amounts of reactants and solvents. This is necessary for adequate mixing and heat transfer. Solvents, when feasible, are recovered and reused. As discussed later, creativity and imagination of the village ^{(8, 9, 10, 11)} for process simplification, reduced solvent use and the ensuing benefits need to be incorporated from the onset. 
 
Chemistries outlined in the patents give us the reaction mechanism for every/most reactive process. We can capitalize on that knowledge to commercialize using most appropriate unit operations ^(3,4) an achieve our environmental obligations ^{(5, 6)}.
 
USP 11,267,798 B2 ⁽¹⁾, luck of the draw, perfectly outlines the reaction chemistry and steps for the production of Piperine. Writing the reaction steps (Figure 1) is necessary as it familiarizes everyone with the reaction chemistry and the process. Reaction intermediates and byproducts are identified. Based on their chemical nature, methods for safe handling and disposal can be selected. Stoichiometry shared in the patent is just an example of what has been used to create a product and generally are not optimum.  
 
With creative application and combination of unit processes ⁽²⁾, unit operations ^{(3, 4)} and reaction kinetics ⁽¹²⁾ manufacturing process of piperine can be simplified. It is possible that the practitioner might have to move away from the tradition of moving away of fitting new reaction chemistries in the existing equipment. Such a move might necessitate deviating from tradition.  
 
Preparation of (2E)-1(1-piperridinyl)-2-buten-1-one (Example 1):
 
To a well stirred mixture of crotonic acid (100 gms, 1.16 moles) DMF (1.0 ml) in dichloromethane 500 ml was added thionyl chloride (100 ml, 1.34 moles) dropwise under N₂ atmosphere at 25-30° C. and stirred for 14 hours at 30-35° C. After completion, reaction mass was concentrated and diluted with MDC (1000 ml) and cooled to 0° C. Piperidine (310.0 ml, 3.15 moles) was added drop wise over a period of 3 hours below 10° C. The reaction mixture was then agitated at 25-30° C. for 7 hrs. After completion, the reaction mixture was filtered and filtrate was sequentially washed with water (2×500 ml), 5% dil. HCl 500 ml, 5% sodium bicarbonate (500 ml) and finally with brine solution (500 ml). Organic layer was evaporated to obtain title compound as dark brown colored oil.
 
Yield: 110.0 grams     HPLC Purity: 95%  Yield of Example 1 step: 61.9%

                                

Figure 1: Scheme 2: Synthesis of Piperine from Crotonic Acid USP 11,267,798 B2 ⁽¹⁾

 

Preparation of (2E)-1(1-piperridinyl)-2-buten-1-one (Example 2):

 

To a well stirred mixture of crotonic acid (50 gms, 0.580 moles) DMF (1.0 ml) in toluene (500 ml) was added thionyl chloride (50 ml, 0.670 moles) dropwise under N₂ atmosphere at 25-30° C. and stirred for 10 hours at 35-40° C. After completion of the reaction additional 250 ml toluene is added to reaction mass. Piperidine (150.0 ml, 0.500 moles) was added drop wise over a period of 3 hours below 10° C. The reaction mixture was then agitated at 25-30° C. for 7 hrs. The progress of the reaction was monitored by HPLC. After completion, the reaction mixture was filtered and filtrate was sequentially washed with water (2×250 ml), 5% dil. HCl (250 ml), 5% Sodium bicarbonate (250 ml) and finally with brine solution (250 ml). Organic layer was evaporated to obtain title compound as dark brown colored oil.

Yield: 65.0 gms     HPLC Purity: 95%.  Yield of Example 1 step: 73.2%

Preparation of Piperine (Example 3):

To a well stirred mixture of (E)-1-(Piperidin-1-yl) but-2-en-1-one (100.0 gm, 0.653 moles), benzyl triethyl ammonium chloride (27.0 gm, 0.118 moles) in DMSO (1000 ml) was added piperonyl aldehyde (88.0 gm, 0.586 moles) at 25-30° C. Aq. NaOH (4.7 gm 0.118 moles in 100 ml water) was added drop wise over a period of 45 min. The reaction mixture was then stirred at 25-30° C. for 12-15 hours. After completion of reaction it was quenched in water (5000 ml) and further stirred at 25° C. for 2.0 hrs. The precipitated solid was isolated by filtration, washed with water and dried under vacuum at 55-60° C. to yield title compound piperine as yellow solid.

The crude piperine was purified by crystallization from 500 ml toluene to obtain crystalline solid.

Yield: 89.0 gm.             HPLC Purity: 99.95% Yield of this step: 47.8%

 

Preparation of Piperine Example 8: 

 

To a well stirred mixture of (E)-1-(Piperidin-1-yl) but-2-en-1-one (225.0 gm, 1.468 moles), benzyl triethyl ammonium chloride (67.0 gm, 0.294 moles) in DMSO (2250 ml) was added piperonyl aldehyde (198.5 gm, 1.322 moles) at 25-30° C. The reaction mixture was stirred for 15-20 mins and aq. NaOH (24.0 gm 0.6 moles in 225 ml water) was added drop wise over a period of 45 min. The reaction mixture was then stirred at 25-30° C. for 5 hours. After completion of reaction it was quenched in water (6750 ml) and further stirred at 25° C. for 1.0 hr. The precipitated solid was isolated by filtration, washed with water and dried under vacuum at 55-60° C. to obtain title compound piperine as yellow solid.

Yield: 301.0 gm Yield of this step: 71.87% 

Depending on the route selected Piperine yield based on the above examples could be between 29.6 to 52.6% 

                        

Table 1: Physical Properties of chemicals used in the preparation of Piperine 

 

Analysis of Process Stoichiometry:

 

Information about the process similar to what is illustrated in Figure 1, Table 1 and Table 2 should be compiled for every process step and reaction chemistry. Figure 1 illustrates the reaction chemistry and is of utmost value. Using the information similar to figure 1 the developers can collect every physical and chemical property ^{(8, 9, 10, 13, 14, 15)} of the chemicals used and produced in each reaction step e.g. molecular weight, density, mutual solubilities, boiling/melting point, azeotropic behavior and viscosity etc. Compiled information facilitates every chemist and chemical engineer in creating an optimum process. They can also be considered and used to modify the process. 

 

Information is of utmost importance in the process design, handling, safety, storage and use. They teach us how the chemicals can and need to be handled at every process step. More we know about the chemicals used, intermediates and the final product produced, the task of scale up, design and commercialization becomes easier and is facilitated. Compilation of such information might be considered redundant but is of value and a treasure as long as the product is being produced by the company. Every chemist and chemical engineer can use the information. Using their creativity and imagination can optimize and economize the process. 

 

This information is also necessary for process simplification, design and improvement. It is very possible that some or many of the physical and chemical properties of the chemicals ^{(8, 9, 10, 13, 14, 15)} used and produced might not be readily available from the databases and/or vendors. They might have to be generated internally. A word of caution. Physical and chemical properties ^{(8, 9, 10, 13, 14, 15)} provided by the vendors need to be verified for accuracy. 

 

Table 2 is compilation of theoretical and actual amounts of key chemicals used to produce (2E)-1(1-piperridinyl)-2-buten-1-one and piperine. It lists mole ratios and yields relative to the crotonic acid, selected as the KEY component, in Example 1 and Example 2. Solvents are excluded. Example 2 has less than theoretical amount of piperidine per mole of crotonic acid but has higher yield. Yield variation between the two routes is significant and it suggests a review of the reported information and its validity. Molar ratios for the preparation of Piperine as also illustrated. 

 

Active reactants concentration in the total reaction mass is about 20% in each reaction. What can be done to conduct the reaction at higher concentration and what would be the result? Generally active concentration of key raw materials is low and that is based on tradition. Based on the chemistry and chemical engineering fundamentals and creativity alternates to do the reaction at higher concentrations ^{(8, 9, 10)} need to be explored and tested.  

 

Another word of caution when acquiring chemicals from different vendors. They generally want to know how and where their product will be used. General answer should be “chemical synthesis” rather than pharmaceutical. Some vendors even go to the extent of signing confidentiality agreements before Moment they know use of chemical is for a pharmaceutical synthesis, prices go up. Their rationale is pure chemical will produce higher purity product. This is not true as the product developer/producer will produce and process the product to meet their own specification. Supplier has to meet buyer needs to produce a product that meets their quality standards. Commercially available raw materials are competitively priced and generally suppliers make every effort to make a deal.  

 

USP 11,267,798 B2 ⁽¹⁾ suggests Piperine can be purified using toluene or isopropyl alcohol with yields ranging from 79.2-80.5%. This suggests that an optimum process can be developed. Every astute chemical engineer and chemist for the subject patent using unit operations ^{(3, 4)} can figure out how to handle evolved SO₂ and hydrochloric acid gas. Use of eductors and inline scrubbing is a possibility. Creativity and imagination is needed ⁽¹⁰⁾. 

 

Based on my experiences I would expect a reasonable excess of piperidine used per mole of crotonic acid for both examples. Molar ratios of piperidine to crotonic acid in examples 1 and 2 in Table 2 need scrutiny. Using different process schemes piperine overall yield varies between 29.6% to 52.6%. Village team members ^{(8, 9, 10, 11)} should review so much variation. My conjecture is that if they were involved from the onset the overall process yield higher than ~75% could be achieved. Even if the process is not going to be commercialized each chemical process development becomes a fertile training ground for excellence. 

Table 2: Relative ratio of key reactants

 

With the start of development process product cost analysis ^{(8, 9, 10)} of the wet chemistry is a very important exercise that needs to be done. Such exercise allows selection of the most profitable process. Again expertise of the village ^{(8, 9, 10, 11)}can be of great benefit for the process development chemists and chemical engineers as they select the most profitable process. Prices of each ingredient used in the illustrated examples are readily available. My crudest factory manufacturing cost ^{(8, 9, 10)}, without putting lot of effort, piperine factory should be less than $40 per kilo. If the conversion cost of any product is equal to or exceeds the raw material cost, it suggests that the commercialized process needs a rigorous review and redesign. Overall yield of less than 75% also suggests that the chemistry needs to be reviewed.   

Information similar to what is compiled in Table 2 can be used to understand what the patentee is citing in their granted or in-process patent. Compared to theoretical yield of a process chemistry, shortfalls of the process are highlighted right away. I am not a patent expert but based on the variations validity of the patent could be questioned. 

Generally when a process is experimented in the laboratory many overlook the fact that someday the process, if the product has high economic value, will be commercialized and the lab developed processes could pose commercialization challenges. Fundamentals of chemistry and chemical engineering have to be applied from the onset of process development to reduce/minimize process development time. To me laboratory is an important cog in the whole scheme. 

 

Expect for benzyl triethyl ammonium chloride (phase transfer catalyst) all of the organic chemicals used and produced are liquid at 40 ºC or above. Since the reactants and the reaction products are liquid at above 40 ºC, They present an opportunity to minimize solvent use in the reaction and present an opportunity to review the reaction stoichiometry to optimize the yield of each reaction step. 

 

Example 1 & 2 for the preparation of (2E)-1(1-piperridinyl)-2-buten-1-one give us clues. Boiling points of dichloromethane (~ 40 °C) and toluene (110 °C) can be used to advantage by raising the reaction temperature (taking advantage of doubling the reaction rate with every 10 °C rise in temperature ⁽¹²⁾. Every chemist and chemical engineer knows and practices associated value. Generally these considerations come in play only when village ^{(8, 9, 10, 11)} is involved from beginning of product and process development. Reduced reaction time impacts type of equipment used and its investment.  

 

Dichloromethane and toluene reactions are being conducted at room temperatures or near room temperatures for 10-15 hours suggest that value of reaction rate ⁽¹²⁾ is not part of the laboratory experiments. They present an opportunity. Are the low yields due to side reaction products being produced when the reactions are being carried out for prolonged time period? Potential of sequential reactions i.e. crotonic acid  crotonyl chloride (2E)-1(1-piperridinyl)-2-buten-1-one  piperine does exist and needs to be considered. At certain annual production volume a continuous manufacturing ⁽¹⁶⁾ is very possible.  

 

Some could easily say that when developing a laboratory synthesis process all of the information discussed above is not necessary. Some could say lab experiments just illustrate feasibility. Unless an outlier attempt is made from the onset, especially in the synthesis of active pharmaceutical ingredients no process simplification effort is made when a molecule enters regulatory filings. Village’s ^{(8, 9, 10, 11)} involvement is necessary and of great value. Low yield suggests many opportunities. Chemicals that enhance lifestyle have different quality needs and their processes can be continually improved. 

 

My conjecture is that if the laboratory syntheses can be simplified and commercialized the time and investment needed to improve the commercial processes can be significantly reduced. 

 

It is again emphasized that every nuance of the reaction and that includes how and where the chemicals are added, their physical properties ^{(8, 9, 10, 13, 14, 15)} i.e. melting point, boiling point, reaction temperature/s mutual solubilities and/or insolubilities can be exploited and capitalized on to create an excellent process. In the reviewed patent higher temperature reactions are eluded. From these claims it becomes obvious that the process chemistry was tested but the results are not known. Testing reaction at higher temperatures has to become a habit from the start of process development. Village ^{(8, 9, 10, 11)} helps in such exploitations. 

 

It is possible to use crotonic acid as a melt or a solution at appropriate temperature and thionyl chloride can be metered in stoichiometrically controlled amount. Availability of appropriate equipment has to be explored for every chemical manufacturing applications. We are generally not taught or are familiar with many of the equipment that is available from other industries and can be used in the manufacture of fine/specialty chemicals. 

 

In the first reaction step hydrochloric acid and sulfur-di-oxide are the reaction byproducts and have to be removed in a way that they do not impede reaction progress. How they would be removed are different for a batch or continuous process. 

 

It would be ideal if piperidine which is liquid at room temperature can be added sequentially to the reaction mass to produce (2E)-1(1-piperridinyl)-2-buten-1-one. Reaction temperature will have to be maintained at an appropriate temperature to assure all of the liquid mass is liquid. Benzyl triethyl ammonium chloride can be introduced as a solution. Based on the discussion one can conjecture that reaction mass is all liquid and is easy to process and flow control. Piperine being a solid at room temperature can be crystallized using most suitable crystallization process, separated and dried. 

 

Equipment size and processing methodology ^{(4, 8, 9, 11)} will dictate the selected method. Again, companies have to evaluate alternate processes and methods and that includes process equipment design and size to suit their technologies. Strategies that are different from the current methods that have not been considered need to be evaluated. Once we see the benefits of what all has been discussed process development and simplification methodologies become second nature. 

 

Information discussed and reviewed is necessary for process design, equipment design and troubleshooting needs that arise during the life of product being produced by the company. All of the compiled/documented information which includes rationale for its process design and operating methods becomes part of the process design manual, the “Holy Book” for that product. Information complied is also helpful for every regulatory filing, compliance, training and trouble shooting. 

Again, purpose of the analysis of USP 11,267,798 B2 is not to find errors in methods used by others but present my perspective and consider opportunities to optimize, have an excellent environmentally friendly and economic process. Creativity and ingenious application along with combination of chemical and physical properties ^{(8, 9, 10, 13, 14, 15)} and unit operations ^{(3, 4)} lead to excellent manufacturing processes ^{(8, 9, 10)}. This has been proven many times over and can repeated for every active pharmaceutical ingredient synthesis.

 

Girish Malhotra, PE

EPCOT International

1. Phull M. S. et. al. USP 11,267,798 B2 “Process for the Preparation of Piperine”, CIPLA Limited
2. Shreve, R. Norris: Unit Process In Chemical Processing, Ind. Eng. Chem. 1954, 46, 4, 672
3. Unit Operations https://bit.ly/2Rp3Xlu
4. Chemical Engineer’s Handbook, Fourth Edition, McGraw-Hill Chemical Engineering Series
5. Burke, J. What does net zero mean? https://www.greenbiz.com/article/what-does-net-zero-mean, May 2, 2019 Accessed April 27, 2021 
6. Sheldon R.A. The E factor 25 years on: the rise of green chemistry and sustainability, Green Chemistry https://pubs.rsc.org/en/content/articlelanding/2017/gc/c6gc02157c/unauth#!divAbstract , 2017, 19, 18-43
7. Malhotra, Girish: Patents: Should We Change Our Intellectual Property Model/Strategies? Profitability through SimplicityOctober 5, 2012  
8. Malhotra, Girish: Chemical Process Simplification: Improving Productivity and Sustainability John Wiley & Sons, February 2011 
9. 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
10. Malhotra, Girish: Active Pharmaceutical Ingredient Manufacturing: Nondestructive Creation De Gruyter April 2022
11. Kalam, APJ Abdul, Wings of Fire: An Autobiography of APJ Abdul Kalam, Sangam Books Ltd, 1999 Accessed January 31, 2024
12. Levenspiel, O: Chemical Reaction Engineering, John Wiley & Sons 1999
13. Malhotra, Girish: Sociochemicology May 30, 2013   
14. Malhotra, Girish: Focus on Physical Properties To Improve Processes: Chemical Engineering, Vol. 119 No. 4 April 2012, pgs. 63-66
15. Malhotra, Girish: Process Simplification and The Art of Exploiting Physical Properties, Profitability through Simplicity, March 10, 2017
16. Continuous Production https://bit.ly/2Rp3Xlu

Pharma’s Advanced Manufacturing Technologies: REALITY OR FIGMENT OF IMAGINATION

USFDA at least since 2013 ⁽¹⁾ has been promoting use of advanced manufacturing technologies (AMT) and that includes “continuous manufacturing (CM) ⁽²⁾ for the manufacture and reduce shortages of drugs ^(3,4,5). It has held various conversations and even involved National Institute of Sciences (NAS). This report “Building Resilience into the Nation's Medical Product Supply Chains ⁽⁶⁾ is a disturbing as it suggests increasing reliance through foreign relationships. 

 

FDA ⁽⁷⁾ has continued to convince the pharmaceutical industry to use advanced manufacturing technologies (AMT) but seems like no one is buying what it has been selling.

 

What are these technologies is not clear. Do AMT include manufacture of API along with their formulations or anything else? A clarification from FDA was asked from its CDER/OPPQ/Office of Policy for Pharmaceutical Quality. A very terse response was received “they will respond in several weeks”. This is especially enlightening and interesting when FDA has been touting to the world to adopt such technologies. If FDA is trying to promote adoption of better manufacturing technologies, it would be beneficial if they were more forthcoming in addressing asked questions.  

 

Even after all the conversations and congressional hearings and claims that these will reduce shortages FDA’s effort that has not resulted in any progress in commercializing AMTs at the pharmaceutical companies. This basically suggests that this effort is not going anywhere. If after effort of more than five years and millions of tax payer dollars that have been doled out to universities and other institutions nothing meaningful has happened.  It basically suggests that companies are not buying what USFDA is selling.

 

It is ironic that FDA wants companies to incorporate “continuous manufacturing (CM) ⁽²⁾” but has not shared what is its understanding and definition. In the manufacturing world there is an established definition ⁽²⁾. It would be interesting how FDA’s definition compares with the established definition. It also needs to very clearly explain what does it call “drug manufacturing”. Is it just formulation of active pharmaceutical ingredients (API) or combination of manufacture of APIs and their formulations? We have to remember that without API there is not drug. It is just a placebo. 

 

FDA has called formulation of certain cancer cure drugs (limited global population which means limited demand) as continuous processes (CM) ⁽⁸⁾. Involved companies formulate batch produced API to finished products. Since these products are formulated on stop and go basis i.e. batch production ⁽⁹⁾, the underlying question is why FDA distorting facts and calling these processes CM. Is it trying to convince the pharma industry that it needs to change its manufacturing practices? Justification and rationale are needed. Even press has been talking about CM ⁽²⁾ when they have no idea what it means. 

 

Based on formulation and compaction technologies that have been commercial and are used to produce many products, question that needs to be addressed is “why the pharmaceutical industry has not adopted established (more than fifty years) technology “en masse”. Is it lack of experience, business model or regulatory interference or being comfortable and profitable with quality by “analysis paralysis” processes? 

 

It is a well-known fact that industry invents drug products. New and/or existing technologies and methods are used produce quality products. However, FDA’s telling the industry that new technologies need to be approved ⁽¹⁰⁾ before they can be implemented is a deterrent for brand and generic drug industry. No one knows what these technologies are. businesses. With FDA’s staff having minimal to no or minimal experience in product and process development, design and commercializing any drug molecule and their manufacturing processes, it would amount to further delays from the current times in brand and generic products. This is an un-necessary interference and oversight of a company. Question is how FDA will help. 

  

Industry should be meeting the necessary drug performance criterion using the methods and processes it has developed, tested inhouse and would want to commercialize ASAP. Every product goes through three steps a) lab, b) pilot plant and c) commercial scale. This will be true for every product if it will be produced using a continuous process ⁽²⁾. Due to FDA staff’s limited experience suggested pre-approval review etc.⁽⁷⁾ will result is further commercialization delays as they have no hands on experience of process development. This will result in further commercialization delays. If the industry does not see value in this effort they will not change their  existing practices and/or consider any new technologies. 

 

USFDA has to be very clear of the pathway it wants industry to follow to implement new technologies. FDA has to layout parameters/questions regarding the technology it wants to the industry to address along with a timetable. Goal has to be commercialization of drug in minimal time after its efficacy has been recognized by the pharma company and proven. Pathway for brand and generic drug will be different. There is big gap between FDA and industry as no headway has been made to improve manufacturing technologies. Industry has to recognize financial value and they do not see it as they are profitable. 

May be it is time for FDA to consider alternate ways so that the pharma industry’s manufacturing can come to 21^st Century. It has tried to corral and impress US congress using its resources, as discussed earlier, but no one has budged. It is my conjecture that nothing will change unless the pharmaceutical industry (development and manufacturing) gets involved. They would not till they see a return. Alternate presented is my own and not influenced by any “for profit and nonprofit” organization. 

 

Pharmaceutical industry would be enthusiastic and welcoming if products produced using better manufacturing technologies could be commercialized much sooner than the current times for NDA (new drug applications) and ANDA (abbreviated new drug applications). For that to happen the triumvirate (FDA, Pharma companies, and Pharmacy Benefit Managers (PBM)) have to change the current methods. My thoughts are a stretch and will face resistance from each. Most will come from FDA and PBMs. Pharma companies most likely would like them as they will lead to shorter time needed for commercialization i.e. higher revenues and profits.  

 

FDA: 

 

FDA when it comes to NDA and ANDA approval needs to eliminate every pre-approval meetings and that includes any new manufacturing technology introduction and use templates to get information it would consider necessary for their review and approval ^(11,12). These meetings are suggestive that the applicant companies do not know and/or understand what all is necessary for approval and they have to teach FDA what is the rationale and value of their innovations. Once FDA has the knowledge, it is possible that approval times could be reduced from current times ^{(13, 14, 15)}.

 

Is FDA personnel due to lack of their experience in process development, scaleup and commercialization especially in “continuous” API and formulations using these meetings to further delay approvals. Basically this could be considered that FDA is learning on the fly what all is necessary for approval. FDA needs to create its expectation guidelines for every new (NDA) and existing (ANDA) drug each applicant company has to follow. These guidelines would be routinely updated so going forward companies. Assimilation of this suggestion will be difficult for FDA. 

 

Pharma companies: 

 

Pharma companies have to have every “t” crossed and “i” dotted when it is submitting information required by FDA for their NDA and ANDA as if they will consume first tablet that comes of the production line and their life depended on it. For continuous API manufacturing and their formulations it is very likely that pharma’s current manufacturing landscape would have to be changed ^{(16, 17, 18)}. Companies would be challenged by FDA as they might have to familiarize FDA personnel with nuances of continuous manufacturing. Not having any process development, scale up and commercialization experience this can be a challenge. Chemists and chemical engineers will need company support, a challenge.  

 

PBMs:

 

For Pharma companies to get excited about consideration and incorporation of newer and better manufacturing technologies, in addition to faster approval than current times, they should be allowed to direct market their FDA approved products by bypassing the formulary lists. Patient and physician should be deciding which approved drug they want to use. PBMs should not be interfering in patient’s life. Having a choice of drug would bring highest quality product at the best price competition to market. Competition is healthy and good for encouraged. PBMs are not required to meet quality standards. They should be held accountable ⁽¹⁴⁾.

 

Yes in the final analysis suggestions made here could be considered radical and not to the linking of parties involved. FDA has been going around with all sorts of permutations and combinations but nothing meaningful has materialized. It has not created an environment to innovate. Pharma industry has ignored FDA’s suggestions. PBMs have no interest in reducing shortages. Unless the accountability is shared by each party involved, US drug system (manufacturing, approval and distribution) have and will limp along and patient will continue to suffer. 

 

Path forward:

 

With FDA’s effort of more than eight years, no progress has been made to incorporate proven better manufacturing technologies used elsewhere in API manufacture and their formulations. Pharma manufacturers are comfortable with the current methods that have been in use from 1940-‘50s as they are profitable ⁽¹⁸⁾. PBMs have no interest in what manufacturing methods/technologies are used as they just sell/distribute drugs to patients at their partial monopoly prices. Shortages have become way of life. An outlier approach is needed if we want to reduce shortages and include better manufacturing technologies. 

 

FDA could promote the modified filing process with a stipulation that companies will have faster approvals than the current times i.e. higher profits. As part of the buy in for shorter approval time, FDA could use its legislative clout and bypass the current marketing channels i.e. formulary constraints. Manufacturers would offer the drugs to patients through alternate channels. PBMs will resist these suggestions as their stranglehold on generic markets would be influenced. 

Suggested pathway should encourage generic manufacturers to invest in better manufacturing technologies i.e. continuous API manufacturing and their formulations. If FDA’s test with generics is a success, it could be extended to brand drugs. Yes brand drug product and process information requirements for approval will be different but the current logjam of slow action will be broken. 

 

FDA would need to start the approval simplification process by creating templets that detail information needed for approval. Creation of information asking templets ⁽¹⁴⁾ could be test of FDA’s internal knowledge and competence. There could be significant internal resistance as the review and approval methods would change. FDA’s pre-meetings etc. would have to be curtailed. This would place the onus of convincing FDA to grant the approval. Companies have more to lose if they do not receive timely approval. Such a change is needed if we collectively want to simplify the age old process. To implement the suggested change FDA may have to avail congressional help, if necessary.

 

Companies may include additional information, some of it could be redundant. Excess of submitted information may help the approval process. In the proposed process FDA personnel will still have an opportunity to ask for additional information ⁽¹⁴⁾to complete the review resulting in grant and/or denial. Review and grant process will have defined time window. Once ANDA is approved certain restrictions could be placed on the filing company i.e. it cannot transfer the approved ANDA to any other profit making company in the next twelve months and it has to produce the product for sale in USA within 1-4 months of the approval. Success with generics could be applied for brand drugs.

 

Since companies will have FDA decision in a finite time rather than unknown time, they should be enthusiastic about the suggested process. They would be able to commercialize their manufacturing process innovations and get a better return on their investment. Yes in the final analysis suggestions made here are radical and may not to the liking of some  involved. 

 

FDA and US Congress have been talking and making noise but no solution has been proposed. As suggested earlier chemical engineers are not practicing unit processes ⁽¹⁹⁾ and unit operations ⁽²⁰⁾ they have been taught to the fullest extent. The process outlined ^{(16, 17,18)} will allow them to incorporate them and create excellent processes to produce quality products. It is time pharma manufacturing comes of age. 

 

Product and manufacturing process technology innovation comes from pharma companies. They do their first part but as said earlier dur to profitability they have lagged on the second part. Unless responsibility to reduce shortages is shared by each party involved, US drug system (manufacturing, approval and distribution) will continue to limp along and patient will suffer. It is time to consider better alternate processes to reduce shortages that include better manufacturing technologies and alternate drug distribution model. We have the minds and chutzpah to excel. Time is now.  

 

Girish Malhotra, PE

 

EPCOT International 

 

References:

1.     Strategic Plan for Preventing and Mitigating Drug Shortages  Accessed March 31, 2024 

2.     Continuous Production

3.     TESTIMONY OF JANET WOODCOCK, MD December 10, 2019

4.     Agency Drug Shortages Task Force October 30, 2019 https://www.fda.gov/drugs/drug-shortages/agency-drug-shortages-task-force

5.     Malhotra, Girish: Identifying the Root Causes of Drug Shortages and Finding An Enduring Solution, Profitability through Simplicity, December 7, 2018

6.     Building resilience into the Nation’s Medical Product’s Supply, National Academy of Scienceshttps://nap.nationalacademies.org/read/26420 Accessed April 22, 2022

7.   Advanced Manufacturing Technologies Designation Program, Guidance for Industry, December 2023 https://www.fda.gov/media/174651/download   

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

9.     Batch Production https://en.wikipedia.org/wiki/Batch_production

10.  Lifecycle of an Emerging Technology Program (ETP) https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/lifecycle-emerging-technology-program-etp

11.  Malhotra, Girish: Can the Review and Approval Process for ANDA at USFDA be Reduced from Ten Months to Three Months? Profitability through Simplicity, March 25, 2017

12.  Malhotra, Girish: What Is Needed for a Regulatory Approval of NDA/ANDA Filings in 90 Days? Profitability through Simplicity October 24, 2018 

13.  Malhotra, Girish: Strategies to Increase Generic Drug Competition and Bring Manufacturing to The United States of America, Profitability through Simplicity, March 16, 2020

14.  Malhotra, Girish: ONE PAGE Road Map to Reduce Drug Shortages, Assure Quality and Improve Affordability, Profitability through Simplicity December 6, 2019  

15.  Malhotra, Girish: Roadmap to Reduce Drug Shortages Profitability through Simplicity October 30, 2023

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

17.  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

18.  Malhotra, Girish:  Active Pharmaceutical Ingredient Manufacturing: Nondestructive Creation DeGruyter April 2022

19.  Shreve, R. Norris: Unit Process In Chemical Processing, Ind. Eng. Chem., 1954, 46 (4), pp. 672–672

20.  Unit Operation, https://en.wikipedia.org/wiki/Unit_operation , Accessed July 11, 2017