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
Pharmaceutical, Specialty and Fine Chemicals and Coating process and manufacturing technologies have to be simple to have the best possible process. Processes have to be safe and best of the methods need to be included to minimize the environmental impact due to air, water or soil discharges. Conservation is a necessity. Simple and good technology will result in a profitable and consistent quality product. This is the intent of every developer, chemist and chemical engineer.
Friday, October 15, 2010
Friday, October 1, 2010
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
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
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