Pharmaceutical Companies Can Innovate If They Want To

Pharmaceutical companies including API (active pharmaceutical ingredient) manufacturers have an uphill battle to achieve manufacturing perfection that will deliver quality product without regulatory oversight. I believe that the industry has created this regulatory juggernaut due to its inability to produce consistent and repeatable quality products.

Recent case of Johnson and Johnson was a failure of manufacturing and financial controls that are the fundamentals of good business. There are other similar incidents where the products were contaminated. Due to such repeated occurrences, regulatory noose gets tighter. Since industry created the juggernaut, it can and has the ability to loosen the noose provided it “rights” its practices.

Since the drugs are for human consumption, the manufacturers have to be reined in to assure quality. This has led to the establishment of “do and don’t” guidelines i.e. analysis paralysis. Industry besides inventing new molecules is more focused on how to meet and comply with the guidelines and regulations rather than developing and commercializing processes that are based on “best of the best” physical and social sciences (chemistry, physics and economics) i.e. chemical engineering.

Brand companies have lived with speed to market. Since they can make their financial margins and generics will take over the business, their thinking has been to invent new molecules and not to invest in new and better manufacturing technologies for the products that are short lived in their stable.

There are other factors that inhibit pharmaceutical companies to have the “best of the best” manufacturing processes for the manufacture of drugs. They are:

1. Drug pricing is based on the highest price customer will pay. Since companies can achieve their financial goals, there is no economic incentive to improve manufacturing technologies.

2. Due to drug dosage, annual volume of the drug per plant per year can be very low.

3. Companies have relied on fitting the process in the existing equipment. This has not resulted in having an optimum process for the products and can result in variable product quality. This is one of the causes that have lead pharmaceutical companies to the current state.

4. Ability to pass on the costs associated with inefficient processes to the customers.

5. Lack of competition during the patent period and also after the patent expiration. Later is due to the regulatory and other economic challenges companies have go through to commercialize drugs. Unless the volume is very large few venture the field.

6. Ability of the companies to recall any “off-spec” products from the market without much retribution.

All of the above collectively and individually can be overcome if the companies create excellent processes based on good physical sciences for the “new products only”. If done right they will improve the total business process such as inventory turns, minimize in-process testing and accumulation of intermediates.

Regulatory and financial investment is a deterrent to manufacturing technology innovation for the existing products. However, Generics can innovate manufacturing technologies for existing products as well as the products that are transitioning out of patent i.e. new generic products. They have incentive as they are there for the long haul.

There are possibilities and opportunities. We have to look at them individually and collectively. Some of them are listed as follows.

1. Improving raw material inventory turns by ensuring raw materials do not have to be tested and can be used “just in time”. There are ways this can be accomplished.

2. Improving and/or eliminating intermediate isolation and storage by completely eliminating in-process sampling and testing i.e. the process will have to be perfect and repeatable at every step.

3. Use of high-powered analytical instrumentation during development of API and drug formulation is necessary. However, we need to develop tests that are simple to give us the necessary answers in the shortest time. We do not need a rocket launch procedure when we can walk ten feet or need to use a Lamborghini when a bicycle would suffice.

Many of the puritans might not agree with my simplifications and perspective. Unless we try to simplify and take command of the processes and produce repeated quality product, regulations will prevent us from manufacturing innovation and simplification. Many of us may remember the jingle “Try it, You'll Like It”.

A systematic and well-orchestrated methodology can be developed and incorporated for pharmaceutical manufacturing. All of the elements exist. If done properly we can move from regulation-based manufacturing to science based and driven manufacturing. Science based technologies will produce consistent and repeatable quality product that will become the norm rather than the exception. Total business process (inventory turns, cash flow and capital investment) will improve and be simplified. In addition, processes will be economic and sustainable.

Girish Malhotra, PE
EPCOT International

Related Articles:

1. Malhotra, Girish: The Path Towards Continuous Processing, Pharmaceutical Processing
2. Malhotra, Girish: Process Centricity is the Key to Quality by Design, Profitability through Simplicity April 6, 2010
3. Malhotra, Girish: Pharmaceutical Costs, Technology Innovation, Opportunities and Reality, Pharmaceutical Processing, February 2010 pgs 20-24
4. Malhotra, Girish: Alphabet Shuffle: Moving From QbA to QbD - An Example of Continuous Processing, Pharmaceutical Processing, February 2009 pg 12-13
5. Will Chemical Engineers Save Pharma? Pharmamanufacturing.com April 10, 2009
6. Malhotra, Girish: API Manufacturing: A Road Map for Green Chemistry and Processes; pharmaQbD.com October 14, 2008
7. Malhotra, Girish; API Manufacture-Simplification and PAT; Pharmaceutical Processing, November 2005, Pages 24-27

Are The Rules A Constraint to Innovation, Competition and A Cause of Adulterated Product?

Rules are generally created to be followed. They maintain discipline. To innovate many times they are broken intentionally or unintentionally. Such forays lead to the creation of new rules. However, if the rules to be followed are cumbersome or become cumbersome, they can be a deterrent to innovation and competition. Companies need to maintain profitability while following complex rules that are difficult to comply with could ship marginally unacceptable product to the market. Such a practice would be violation of the public trust.

A review of the proposed US FDA guidelines for “Process Validation: General Principles and Practices” suggest that the rules are complex. They instead of simplifying manufacturing operations will add complexity to the business operations. At times I wonder has anyone done a dry run and economic value analysis of the proposed or even of the adopted rules on any commercial process. The proposed rules will drive manufacturing by “regulatory centricity” rather than “product centricity”. “Process and product centricity” are needed rather than “regulatory centricity”. It will take an army of technocrats time to prepare, fill and comply with the regulatory paper work. My estimate is that it will be more than the time needed to simplify and/or develop complying processes.

It seems that the regulations are being used to produce a reproducible quality product using a less than efficient process rather than having an efficient and a process from the onset that will produce repeatable quality product. Simply said the rules dictate how and what of every step of the potato peeling process needs to be documented rather than assist in creating a simple, safe and sustainable process that will result in a repeatable quality product.

“Section III. Statutory and Regulatory Requirements For Process Validation” of the proposed “Process Validation: General Principles and Practices” rules got my attention. It states the following:

“Process validation for drugs (finished pharmaceuticals and components) is a legally enforceable requirement under section 501(a)(2)(B) of the Act, which states the following:

A drug . . . shall be deemed to be adulterated . . . if . . . the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess.”

If the Federal Food, Drug, and Cosmetic Act gives the US federal government legal enforceability option then why is the government not enforcing its legal obligation for its citizens when it comes to drugs that do not comply with specifications or are contaminated with foreign substances.

Marketing and formulation companies through their alliance market a product that meets specification and has to be produced following the rules. In the recent years we have seen increasing amounts of unacceptable product in the market. It could be due to increased amounts being outsourced and the companies are not able to or want to follow the complicated rules. If the product that does not meet the specifications shows up in the public domain it is violation of the company’s committed public obligation and trust. A question needs to be asked, “Why are the companies failing in their public commitment?”

Governments have allowed recalls of bad product hiccups. If a commercialized material does not meet agreed specifications, could the distribution of “off-spec” products be considered criminal offence by the pharmaceutical companies as they have failed to adhere to the established standards? Could the complexity of rules that outline how, what and why of manufacturing allows some of the product slipping through the quality checks in place? Could the rules act as a deterrent to competition and also prevent innovation in pharmaceutical manufacturing processes?

Our objective should be to simplify the rules and the processes that will foster innovation and competition through manufacturing simplicity and produce a consistent quality product all the time.

Girish Malhotra, PE
President
EPCOT International

The Importance of Fundamentals

Globally Johnson & Johnson is known for its integrity and product quality. Few years ago they handled the Tylenol situation extremely well and were commended for it.

It is astounding that Year 2010 has become a nightmare for Johnson & Johnson. It is heart breaking to read a statement “Certain over-the-counter (OTC) Children’s and Infants’ liquid products manufactured in the United States have been recalled as they may contain a higher concentration of active ingredient than is specified; others may contain inactive ingredients that may not meet internal testing requirements; and others may contain tiny particles.”

Overage of active ingredient and inclusion of tiny particles is simply failure of the people to do what they are supposed to do at any manufacturing operation. In any manufacturing operation people design, operate and maintain equipment to ensure that the process operates as designed. It is a good manufacturing practice to calibrate the equipment routinely to ensure that the equipment is operating as designed. Filters get replaced on a routine basis. In addition, a mass balance is made by every chemical blending operation to make sure the process is being operated at standard or better. Mass balance and cost calculations if done you on a daily, weekly or as chosen basis tell you if your costs and material usage are on track.

Any overuse of materials will show up as the material cost being higher than standard cost and will also show up as inventory shrinkage. Higher than standard cost will be a financial variance i.e. the operation is loosing money on the product. Inventory shrinkage also shows up as a financial variance. In the case of Johnson & Johnson or any manufacturing company the two safety nets, that are supposed to catch overuse, failed. In layman terms, they lost money i.e. someone was sleeping at the financial desk.

Overuse of active ingredient and contamination of particles in the product suggests that on the operations side the manufacturing, maintenance and quality control functions also failed.

What happened at Johnson & Johnson is a gross malfunction at a Global Fortune 125 company. It seems that many at J&J forgot to apply FINANCIAL AND ENGINEERING fundamentals. Based on what I have read, it seems profits took precedence over quality. Their “Quality Czar” will have his hands dirty as he cleans the house.

Girish Malhotra, PE

President
EPCOT International

Square Plug In A Round Hole: Does This Scenario Exist in Pharmaceuticals?

“Square plug in a round hole” is a statement about situations that do not fit in normal life but under the right circumstances we can live with them. If this happens in a manufacturing operation, common wisdom is that money is lost on such a product/process and it would not be commercialized. However, if it happens in an operation where the money can be recovered by passing the inefficiency costs to the customers, would any one worry? Probably not! It would be worth exploring if such a scenario prevails in the manufacture of pharmaceuticals.

Chemists/Chemical Engineers develop an optimum (quality by design) process for an active pharmaceutical ingredient. During the scale up and commercialization process they find that they do not have the right size equipment and/or the configuration that exacts their desired process. However, there is a high demand for the product. Considerable monies can be earned if we produce and market this product quickly without large investment. We can alter the process or modify the existing equipment at a minimum cost to fit the process in the available equipment. The product is being produced in equipment that is not a perfect fit. It requires continuous quality analysis and equipment cleaning to minimize contamination. Would such a process be an example of “square plug in a round hole”? Further analysis might be helpful.

Based on an optimum heat and mass balance for an active pharmaceutical ingredient (API), we need equipment of size and configuration “X” to produce the product at the lowest cost. Many manufacturing sites do not have the exact size and configuration available. However, we have equipment of size and configuration “Y” and our process could be modified to fit in it. With necessary modifications product of the desired quality can be produced. The costs would be higher than the costs of an optimized process. Product produced by such processes would require repeated analysis of the intermediates and the final product to ensure our process and equipment would deliver the desired quality product. Necessary manufacturing protocol would have to be strictly followed and enforced. Equipment would have to be thoroughly cleaned between batches. All of the associated manufacturing costs will be passed on to the customer. Due to high demand the product could be produced at different sites. The process or the equipment would have to be modified to fit the local situations.

Since we have force fitted a process in equipment that is not specifically designed for it, I would call such a process “square plug in a round hole” that has opportunities to lower costs but since the company is able to meet or exceed their profit margins lowest cost optimized process considerations and process innovation become irrelevant. Under these circumstances we also overlook “square plug in a round hole” connotation.

In the above scenario “quality by analysis” becomes a way of life. Pharmaceuticals are living in such an environment. Since the companies are able to demonstrate product quality repeatability, meet regulatory guidelines and achieve their profit margins having an optimum process or practicing the best manufacturing technology is not necessary. What do you think?

Girish Malhotra, PE

President
EPCOT International

Pharmaceutical Reverse Payments and Lower Drug Costs: An Interesting Dilemma!

US Federal Trade Commission and the lawmakers have scorned “reverse payment” also called “pay-for delay” in the pharmaceutical business. US House of Representative recently voted 239-182 to restrict such payments in the hopes that stopping such payments will reduce the cost of drugs to the consumer. Legislators would like to see the drug costs lowered for their constituents. Everyone had expected that the entry of generics would significantly reduce the drug prices. Generics have put some pressure on brand companies but their presence has not lowered the costs of drugs by significant percentage.

US Federal Trade Commission estimates that the “reverse payments” could save US customers about $ 3.5 billion dollars per year. These savings might be there but they are not worth the effort and squabble compared to the yearly US drug revenue of about $480 billion dollars. These payments are less than three day’s revenue. Since every company wants to maximize their profits for the patented drugs, use of “reverse payment” is part of doing business. These costs are passed on to the consumer. In US customers, who are covered by a health plan do not know the real prices of the prescription drugs they just pay the co-pay.

Legislation is not going to lower the drug costs. Fundamental reason for the companies to be in the business is “profits”. If any government limits the profit margins or sets the prices, they that will be in direct conflict with the charter of every company i.e. to have the highest profits. Government’s price control would discourage innovation.

We need to understand the factors of prices/costs, how they can be lowered and passed on to the consumers. Underlying fact is that all of us want to extend our life and we will pay anything for that. Drug prices are based on this sentiment. Prices are set at the highest level companies believe customers can afford. Every company in the supply chain has used this sentiment for pricing. This also covers inefficiencies of the companies.

Limiting profits is against the economic principles. Laws of economics teach us that in a fair game, only competition can lower prices. Brand companies have lowered prices when they want to promote and/or grab the market share as evidenced by recent price drops in the selected developing countries. In the recent years limited number of prescription drugs are available from well-known merchandisers [$4.00 for 30 day and $10.00 for 90 day supply]. This is a clear indication that the drug prices can be lowered and everyone in the supply chain can make their desired profit.

Regulatory and appropriate government bodies have to facilitate competition. Companies in the supply chain also have to participate in this endeavor. Lowering of drug costs to the consumer by 8-10 percent or higher will have value for consumers provided they are passed on. Less than one percent cost reduction is of no value. Addressing minor issues like “reverse payment” just placates the constituents without accomplishing anything and upsets the brand pharmaceutical companies.

Real issues that will lower the drug costs need to be addressed and no one is addressing them.

Girish MALHOTRA, PE

Microscopic Examination of Indian Pharmaceutical Acquisitions by Multinational Companies

Brand companies establishing beachhead in India is a logical choice as they see access to market to growing at 10+ percent. India is source of revenue and profit replenishment for the multinationals. End result of such acquisitions is going to higher drug prices for the masses or government intervention. It would be interesting to see what develops.

There is an underlying question about the sales of Indian pharmaceuticals companies. Why?

Since 2005 Indian companies have challenged the multinationals and have forced a landscape change. Why are the companies being sold now when they have created very successful franchises? One could say the price was too good to refuse. May be, but has anyone considered another reason i.e. lack of succession in the entrepreneur families or letting the trained managers run and grow the companies to compete with the brand companies.

Singh family (Ranbaxy) allegedly had family feud and they brought in Dr. Brian Tempest to cool the storm. However, under Singh family regime there were lapses as manifested by US FDA’s actions. Were the lapses beyond control to fix? Under these circumstances Singh family got an offer they could not refuse. Could that be the case with Piramal family?

Consolidation within India i.e. one successful company buying other pharmaceutical company is not in the culture. Thus unless there is strong succession planning, we will see repeats of Matrix Labs, Ranbaxy, Shantha Biotech and Piramal Healthcare.

If the entrepreneur families do not pass the baton to trained professionals, I believe Indian pharmaceuticals, API (active pharmaceutical ingredient) companies, formulators and other associated with the pharmaceuticals could be selling out to MNCs. It will be a case of take your money and run.

Process Centricity is the Key to Quality by Design

It would be worth reviewing future of pharma’s most discussed acronyms (PAT, QBA and QBD). The following are my interpretation of these acronyms.

PAT (Process Analytical Technologies) means various analytical methods that can be used to convey the state of the sample as soon it is tested.

QBA (Quality by Analysis) is a methodology where the intermediates are tested by “off-line” sampling. The results tell us an “after the fact” state of the manufacturing process. Repeated testing is used to tweak the process till the desired quality product is produced. Such testing is manifestation of lack of complete understanding of the chemistry, process, equipment and any and all variables that interact to produce a product.

QBD (Quality by Design) tells us that the people, who have developed and designed the process, have complete understanding of the process, equipment and their interaction as the sample tested would meet specifications any and all the time. No intermediate sampling is necessary.

Around 2001, the above acronyms were coined for the Pharmaceutical world. They were an instant buzz and synonymous with the current and future state of manufacturing. However, based on reading much of the published literature, I get the impression that “PAT” is considered a cure all and by waving this magic wand, we will produce quality product all the time. This is far from reality.

Published literature also suggests many differing interpretations of these TLA’s and that could be the one of the reasons for very little progress toward QBD adoption.

Any analytical equipment, that costs more than $30,000 (just a number) and requires an analytical chemist to operate and interpret the results for a commercial operation, is expensive. As stated earlier an intermediate process sample tells the state of the sample tested i.e. is the process on track or not. This testing will not and cannot fix the manufacturing process automatically unless the analytical equipment delivers real time results and has feedback loops to control the process stoichiometry and operating conditions. In order to have this level of process sophistication one has to have complete understanding of the chemistry, process equipment and operating conditions i.e. one has to move from “chemistry centricity” to “process centricity”.

What is process centricity? Process centricity to me means moving away from “chemistry centric” laboratory practices and commercializing unit processes by applying appropriate unit operations. This would allow operating personnel to have complete command of the chemistry, process equipment and operating conditions. They can create a process error, observe the process change and can correct the error in minimal time without producing off-spec product. Chemists and chemical engineers have to have incorporated this level of knowledge in the process. This would be perfection (almost) and will not require complex analytical methods to check the process and the product, as we will produce quality. We will achieve QBD i.e. NIRVANA.

Since majority of the APIs are fine/specialty chemicals, their manufacturing practices are very similar. Due to dosage needs the API annual manufacturing production volumes are significantly different from fine/specialty chemical volumes. Thus, it is necessary that we evaluate the current manufacturing practices. Process centricity might necessitate that we change/alter API manufacturing practices. We have to implement methods that are simple and based on good chemical engineering principles and practices. Technologies and methods exist to achieve this change but due to “chemistry centricity” we have not made any significant progress.

As I have explained in a recent article and blogs companies most suited for implementing “Quality by Design” are the API producers and the formulating companies. They have to move away from “chemistry centricity” to “manufacturing centricity” during the technology transfer and incorporate methods that do not require any intermediate product sampling and analysis. This might not look or sound easy, but is the only way to produce a product based on “quality by design”.

It is a bit disheartening for many that almost after ten years, we are still discussing PAT, QBA and QBD. If more than 51 percent of the API producers and formulators stop intermediate sampling, I will consider QBD would become a way of future life in the pharmaceutical world. If this does not happen soon (let us say in the next two to three years) my conjecture is that PAT, QBA and QBD will disappear from the pharmaceutical vocabulary like any other fad. That would be sad because we collectively would have failed to implement a good idea that not only will improve profits but also might facilitate regulatory requirements.

Girish MALHOTRA, PE
President
EPCOT International

Alternate Interpretation of Pharmaceutical TLAs; Three-letter Acronyms

Around 2001 Dr. Ajaz Hussain and his colleagues at USFDA-based on their experiences-suggested and encouraged the global pharmaceutical industry to improve their process technologies so that the manufacturing practices could be simplified and quality products produced with minimum interference. It has been a noble effort and led to the coining of two acronyms QBA and QBD. Based on the amount of printed material, I have seen considerable analysis and discussion on how to move from “A” to “D”. I would like to restate these acronyms differently in a lighter perspective with the hope that we will improve our manufacturing technologies.

In the current state of manufacture of active pharmaceutical ingredients (APIs) and formulated products, we repeatedly check intermediates and the final product for quality. This practice has been appropriately called “Quality by Analysis” (QBA). It not only prolongs the manufacturing cycles and processes but also impacts the whole business process through increased inventories of raw materials, in-process materials and finished goods. The whole business process becomes complex and lowers profitability.

I would like to rename the acronym QBA and call it “Quality by Aggravation”. Why aggravation? Meticulous sampling and analysis is necessary to ensure we follow protocol at each step. This prolongs and extends the batch cycle times. Everyone gets aggravated if anything is not done as per procedures. Intermediate product not meeting specifications either is reworked or disposed of. All this costs money. In addition, it increases work in process inventories that affects the cash flow. Additional investment could be needed to quarantine intermediates and all this lower profits. In doing all these we aggravate our life and it has been our way of life.

Aggravation (mental and financial) in pharmaceutical manufacturing processes can be alleviated if we have complete command of the process chemistry and its unit operations so that we can produce quality product with minimum or no intermediate samplings. Since we will produce products based on “quality by design” QBD, I would also like to rename this acronym to “Quality by Desire”. We will have quality production. This will simplify manufacturing process and life. Our desire to have an excellent process could significantly reduce our aggravation. It even could be eliminated.

Pharmaceutical products have to meet the strictest of the quality standards no matter how the products are produced. The question that needs to be put on the table is what should be our method of choosing to produce a quality product. “Quality by Aggravation” or “Quality by Desire” are the two choices and we have to pick one.

Most of us know the correct answer. All of us have a choice and can do what we desire. Since maximizing profitability is the ultimate goal, I am not sure why we have avoided the right path for so long. Is the industry waiting for disruptive innovation?

QBA and QBD methods are applicable to everything we do in life. When we desire anything, we make sure that our methods to achieve the goals are swift and simple. We always pick QBD. Our choice in the manufacture of pharmaceuticals and their components is “Quality by Aggravation” or “Quality by Desire”. You pick.

Girish Malhotra, PE
President
EPCOT International

HIV Drug Availability and Potential Manufacturing Opportunity

Global spread of HIV/AIDS has been and is a cause of alarm. Approximately 33.4 million people are estimated to be infected with HIV/AIDS and about 30% of this population can use the antiretroviral therapy (ART). Of this number about 42% are getting the treatment. This could be due to pricing and/or their availability or a combination of both. There are methods and means to lower the cost and increase availability. I have used AZT (Azidothymidine/Zidovudine) an ART component as an example to illustrate the need for manufacturing technology innovation that can lower prices and increase availability.

In general majority of the active pharmaceutical ingredients (API) are manufactured using batch processes. This is more due to tradition rather than the process chemistry and economics. This holds true for high and low volume actives. Some of the actives due to their chemistry and volume have become commodity chemicals and are produced by continuous processes. However, batch processing is still the preferred method of API manufacture in China and India irrespective of their volume.

Under Clinton Foundation HIV/AIDS Initiative (CHAI), prices of some of the HIV/AIDS drugs have been negotiated with the suppliers from India and China. AZT (300 milligram) tablet is priced at 13.3 cents.

Doing a reverse calculation and using about 80% tablet formulation yield, one can calculate potential bulk selling price of the azidothymidine. Using two 300-milligram tablets per day about 2.4 million pounds of azidothymidine would be needed for about 4 million patients. At $25.00 per kilo, the cost of the API content would be about 1.88 cents per tablet. If the formulation, excipient cost and profit were considered to be 5 times the cost of API (an estimate), the cost of finished tablet would be about 11.25 cents per tablet compared to 13.3 cents from CHAI. Thus the assumption of $25.00 per kilo for bulk API is not un-reasonable. All of the AZT in the above consideration is produced using batch processes.

In the coming years under the new World health Organization guidelines, if the number of people needing treatment grows to 14 Million, there would be a supply problem. The capacity of the existing batch processes would have to be increased to about 8.5 million pounds of AZT per year. Similar steps would be needed to increase capacity of other members of the ART cocktail. Other alternate is to develop and commercialize continuous processes.

A continuous process would not only increase throughput but also will lower the manufacturing cost and consistently produce product of high quality. Combination of improved manufacturing technology and throughput can easily lower costs by 20-25%. Based on the reported chemistry, it should be feasible to develop a continuous process. We should never forget that most of the actives are fine chemicals first and drugs second. Acceptance of this fact might facilitate development of better manufacturing technologies. If better technology drops the price of AZT from 11.25 cents per tablet to 9 cents this would be a significant improvement.

A continuous process would have much higher throughput than the batch processes facilitating availability of the needed drug. Plants can be ramped up and down to meet the market demand. Three plants using continuous processes and operating at about 400 pounds per hour (24/350 at 85% on-stream-time) could meet the global demand of AZT and give the operators higher profit margin. Strategy discussed above could be extended for other components of the HIV/AIDS cocktail. It would be a win-win.

A Radical Approach to Fine/Specialty API Manufacturing

Average wholesale price (AWP) of blockbuster drugs (sales greater than one billion dollar/year) and dosage determine the quantity of API needed. This calculation can be made easily based on information in the public domain. For a 200 milligram dose blockbuster, a decent process for a certain molecule at $10.00 AWP, would require about 25,000 kilos of API. API need would change with different AWP and dosage. Poor process and yield would mean that their pollution (not just carbon) footprint is much bigger. At $50 per kilo, the API revenue would be about $1.25 million dollars, which is miniscule compared to the total drug revenue. 

Due to low volumes, the global API producers resort to the easy, traditional method that we are taught through our textbooks - batch process. The nature of the batch process diminishes/prevents any implementation of “Quality by design (QBD)” methods and we resort to “after the fact” analysis and fixes, which cost both money and time. This situation is the norm for in pharmaceutical fine chemical manufacturing. 

Due to the price differential between AWP, the factory cost of API and the tablet/capsule, there is little financial incentive for the drug wholesaler to invest in manufacturing innovation. However, the API producer and the drug formulator have a major incentive to improve their profits – being the manufacturing technology innovation leader. However, a production paradigm shift on the part of producers and formulators is needed to achieve that goal. 

Creative incorporation of physical properties and unit processes, as well as manipulation of unit operations and modular plants can facilitate QBD. This will serve to ensure continuous processes producing quality product the first time and all the time. Modular plants can produce almost any combination of fine or specialty chemicals. Since the API volumes are low, they can be campaigned allowing different products to be produced by companies with proficiency or expertise in specific chemistries and/or methods. Entities with knowledge of alternative manufacturing methods can easily produce some of the actives using continuous processes. A properly designed facility can produce about 55,000 pounds of product operating 24/7 at 100 pounds per hour in about four weeks. A batch process can take longer and would require greater investment. 

Fine/specialty chemicals such as 3-(diaminomethylidene)-1,1-dimethylguanidine hydrochloride, 2-[1-(aminomethyl)cyclohexyl]acetic acid, (RS)-6-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl) methylsulfinyl)-1H-benzo[d]imidazole, various Fluoroquinolones derivatives, 2-[di(phenyl)methylsulfinyl]acetamide, 1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)oxolan-2-yl]-5-methyl-1,2,3,4-tetrahydropyrimidine-2,4-dione are a few examples of what can be produced by batch processes. However, continuous processes using modular unit operations can also produce these products. One must be creative and able to effectively incorporate the nuances of physical properties and reaction kinetics into the manufacturing processes. The above chemicals are examples of anti diabetic, anti bacterial, pump protein inhibitor, anti viral compound and other disease curing actives. 

Traditionally, in the development of pharmaceutical fine/specialty chemicals we get enamored with incorporating regulatory practices and guidelines before we have an excellent process that will produce repeatable and consistent quality product without “in-process” analysis of intermediates. This is like trying to fit a square peg into a round hole. For manufacturing technology innovation, we have to step out of our comfort zone. The North American automobile industry, for example, got trapped in its comfort zone with very discomforting results. Chinese/Indian or any other companies could be the “creative destructionist” and change the global playing field. 

Alternative manufacturing technologies and methods will force process efficiencies and lower the pollution footprint. API manufacturers and drug formulators must take the lead in utilizing these methods. Since such methods would be innovative, we could also see reduction or stoppage of job migration to developing countries. With the right technologies cGMP would be a given.

Girish Malhotra, PE

EPCOT International