All opinions are my own.

Thursday, November 19, 2015

Is FDA Rule 21CFR314.70 a Case of “Shackled Freedom” for Pharmaceutical Manufacturing?

FDA rule CFR314.70 is an interesting rule. I believe if the pharmaceutical industry wants to produce quality drugs with minimal or no in-process testing, this rule has to change. I have presented my perspective (1,2,3).

This rule is of significant value as it can improve profitability, expand the patient base by making drugs affordable and get the companies out of the rut of repeated analysis of samples all along the manufacturing processes. However, the rule needs to be simplified.

If done and implemented commercial processes can be improved and best of the chemical engineering and chemistry practices be incorporated during the patent life of the branded products and also for generic products. “Continuous improvement” would become part of the pharma lifestyle. Fundamentals of engineering and science will lead development and commercialization of excellent processes. They will produce quality products. Science would make glorified acronyms (QbA, PAT and QbD) history.

Rule as it exists suggests that companies can change the approved processes but have to share with the regulators everything like what, how, when and where the improvements will be done. This, I would call is regulatory interference and is a deterrent. This I call is “shackled freedom”, companies can innovate but the regulatory red tape becomes bottleneck for innovation. Most likely in the current scenario companies would not do any process improvements. Companies do not have any incentive to improve their practices as profits and their customer base (who-so-ever can afford) are assured even with inefficient processes/methods. Patient will pay to extend life.

For “continuous improvements” and manufacturing technology innovation companies need complete freedom. My recommendation to the rule makers is that the companies be allowed to do so with the stipulation that the produced product has to meet efficacy and performance of the already approved product i.e. bioequivalence has to be assured and demonstrated if desired by the regulators. A trust has to be built between the companies and regulators.

For regulators to give away the suggested freedom to the companies would be like giving away their kingdom, a difficult choice. Since quality of the drugs is paramount, companies will have to give something also to the regulators and that would be if the product quality is not met, the producing operation is shut down, no questions asked. Legal interference could create issues for this give and take.

Who will win?

If suggested is adopted process of “continuous improvement” will set in and it could lead to much needed competition in pharma. Winners will be patients (through affordable drugs) and companies with higher profits (through better technologies). Regulators will regulate. I believe carrot and stick approach will help us all win. Pharma will be able to capitalize on an unprecedented opportunity that has never been offered to any industry i.e. increase their customer base by as much as billion or more. It will be a win-win.  

Girish Malhotra, PE
EPCOT International

2.     Malhotra, Girish: Process of Continuous Improvement and Pharmaceuticals: http://pharmachemicalscoatings.blogspot.com/2009/06/process-of-continuous-improvement-and.html

3.     Malhotra, Girish: Impact of 21CFR 314.70 on The Life of a Pharmaceutical Manufacturing Process: http://pharmachemicalscoatings.blogspot.com/2015/08/impact-of-21cfr-314670-on-life-of.html

Tuesday, November 17, 2015

Calling for Change

My perspective for Pharmaceutical Manufacturing Technologies/Processes and Continuous Improvements


Regulations are necessary for quality assurance of drugs. FDA established 21CFR314.70 (1,2) and it is a very important rule. It assures that there is no “by manufacturer’s choice” deviation from the manufacturing methods and practices that have been filed for the components involved in the manufacture of any salable drug – the active pharmaceutical ingredient (API) and their formulation – and labeling, packaging etc. Every change has to be reported. Drastic process changes are discouraged.

When there is a discussion about pharmaceutical manufacturing generally only formulations are considered. API manufacturing is ignored and it should not be. Without API there is no drug. 21 CFR314.70 encourages “continuous improvements” in the processes that will create the best product for clinical trials and that’s the way it should be. However, in my estimation under the current rules all of this has to be done prior to going to clinical trials. QbD (quality by design) becomes a natural part of the process development before a process is commercialized. After the fact process change is difficult.

Batch processes

Generally, most APIs and their formulations are produced using batch processes. Existing approved products require annual reporting of improvements/changes. Most of the changes are minor. However, if the processes are to be revamped for process yield, operating parameters and  manufacturing methods, they are going to be the biggest challenge as the efficacy of the API and its formulations, especially prescription drugs could change. In my estimation re-approval would be needed. This can be a monumental task, even for over the counter drugs (OTC) not requiring prescriptions, because new monographs may have to be established. Money and time investment would be necessary. Such changes are major “continuous improvements” and deterrent for prescription drugs.

Continuous Manufacturing

Continuous manufacturing for API and their formulations is pharma’s new and least understood buzzword. In the annals of chemical engineering and for that matter in any industry “continuous manufacturing” means 24x7x50 hours of operation per year with pre-established down time. There are few selected APIs (OTC or prescription) that can be converted to continuous processes (3, 4, 5). 

Totally different operational thinking/models would be required. The use of existing manufacturing equipment and technologies is very feasible.

Continuous processes for formulations should have been commercialized over sixty years ago.
Manufacturing technologies and equipment along with knowledge base for such processes have existed since, but not incorporated. This is due to traditions of business and lack of application of chemical engineering knowledge base to commercialize such processes.

Benefits and Challenges of Continuous Improvement

Benefits of cost reduction, improved profits and larger customer base due to improved manufacturing technologies are huge and well documented. Best of the process technologies have to be created before clinical trials. As we know “after the fact” improvements, under the current regulatory environment, would not happen due to the financial and time elements discussed above.

Only a “maverick company or creative destructionist” can take on the task. Success would completely change the pharma landscape. I am not sure if pharma related components and that includes companies, legislature, vested interest groups, are ready for such an evolution.

There will be microscopic examination and doubts raised, forcing many delays even if the companies do the “right” things based on excellent science and engineering.

Alternate Proposal

I would propose the following. I am sure there will be plenty of scrutiny and naysayers – unless we take bold steps not much changes. If there are alternate better ideas, let us discuss those also. I propose that the pharmaceutical industry be allowed to commercialize process improvements (yield, process/operating conditions, operating parameters, cycle time) in the manufacture of approved APIs and their formulations.

The manufacturing company will guarantee that the product efficacy and performance, along with impurities, will be better than the approved product produced by the company. There would be an added stipulation that if for any reason product performance, efficacy, labeling and impurities do not meet or are worse off from the approved product, company proposing improvements will be barred from making the product using alternate process for the next e.g. two or three years. If they do decide to use the alternate process, they will have to go through the re-approval process. Minor changes that do not change the current filed processing methods etc. would be excluded. This would apply to OTC, brand and generic products also.

I propose that the pharmaceutical industry be allowed to commercialize process improvements in the manufacture of approved APIs and their formulations – without re-approval

Unless bold steps are considered, very little will change in the current pharma’s manufacturing methodologies or anywhere, for that matter


I admit that my proposal is a bit bold but unless such bold steps are considered, very little will change in the current pharma’s manufacturing methodologies or anywhere, for that matter. If incorporated in pharmaceutical manufacturing landscape, continuous improvements and innovation could become a routine and it could be extended to the whole healthcare industry. Wright Brothers did and so was the adventure of sending humans to moon and bringing them back. A successful trek to Pluto would also fit the category. It is time for the pharma industry to be bold. It has an opportunity to add as much as 20% of the global population (~1.4 billion) to its customer base, an unprecedented opportunity for any industry on the planet. Profits will improve and healthcare costs can come done. It would be a win-win.

Girish Malhotra
EPCOT International 

This was presented at CPhI Madrid October 2015. 


1. CFR - Code of Federal Regulations Title 21

2. Malhotra, Girish: Impact of 21CFR 314.70 on The Life of a
Pharmaceutical Manufacturing Process, Profitability through Simplicity, http://pharmachemicalscoatings.blogspot.com/2015/08/impact-of-21cfr-314670-on-life-of.html

3. Malhotra, Girish: Why Fitting a Square Plug in a Round hole is Profitable for Pharma and Most Likely Will Stay? Profitability through Simplicity, http://pharmachemicalscoatings.blogspot.com/2014/08/why-fitting-square-plug-in-round-hole.html

4. Malhotra, Girish: A Blueprint for Improved Pharma Competitiveness, Contract Pharma, Vol. 16, 7, Pg. 46-49, September 2014,

5. Malhotra, Girish: Continuous Process in Pharmaceutical Manufacturing: Considerations, Nuances and Challenges, Contact Pharma, June 2, 2015,

Friday, October 2, 2015

Is Pharma’s Goal to Serve Patients Per Billion or Million?

In the pharmaceutical world, week of September 21, 2015 was interesting. Martin Shkreli (1) of Turing Pharmaceuticals raised the price of an old drug (Daraprim) from $13.50 to $750.00 per tablet overnight. Suddenly the high price move is being abhorred. Shkreli’s move and rationale has been equated to greed and arrogance. This has led to all kinds of pro and con comments in press (2,3,4,5,6). Even politicians, who generally are significantly influenced by the pharma lobby jumped out and called for price restraint (7). His explanation for the price increase included from need to make money irrespective of the past selling price to pay for his acquisition of the drug license, lack of customer service and need to pay for high R&D costs to customer service (8). Most likely Shkreli has no clue of the manufacturing cost and what is involved. Having been around for the last sixty years, no R&D is involved. I am not sure what kind of customer service was missing.

Question “why suddenly drug prices are being increased by high multiples?” Dr. Peter B. Bach (9) from Sloan Kettering makes interesting points “To criticize drug pricing is to raise a more difficult question: Is any price too high to save or extend a life? But in the U.S., prices are rising not because they must, but because they can. No entity holds them down. Instead, state and federal regulations require nearly every insurer to provide access to all cancer drugs, which means the companies can charge what they like. Doctors, meanwhile, are trained not to consider the cost of a treatment when making medication choices.” He makes very constructive suggestion on drug pricing “If we want innovation, and we certainly do, the solution to affording it lies in paying only for its value.”

Recently other companies have joined to increase their prices (7,10). Suggested global price variability ($900 to $30,000) for six month Tuberculosis course is astounding (11). There have been other price increases over the years but they were not publicized.   

Most of the pharma conversation in press is generally about preservation/increase of revenue, profits and justification of high R&D costs to develop new drugs even if they were for less than 100,000 patients (about 14 patients per million) worldwide. Drug with sales of one billion dollars per year is considered a blockbuster success even if there are 10,000 patients worldwide (one to two patients per million) paying $100,000 per patient.

Like in every business, pharma also has R&D and manufacturing costs. R&D costs are considered the untouchables. No one wants to accept any other explanation of these high costs as the press information, even if it is wrong, is considered sacrosanct. Discussion of inefficiencies in R&D is off-limits from any conversation.

At times pharma’s high cost are blamed on manufacturing and regulations (12). There is no mention of any effort to lower manufacturing costs or marketing costs. Very few understand the cost breakdown. This is due to lack of understanding of how to calculate the factory costs of the APIs and their formulations. Every inefficiency cost of manufacturing process is passed on to the patients. Patients pay, as they want to live.  

Irony is that in the last few years pharma companies have not developed many drugs for a large patient base (e.g. more than five million) worldwide. Whatever has been developed, as stated above, is for small patient base. They are expensive and covered by mutually subsidized healthcare systems or pay from their own pocket. Some physicians and pharmacy benefit managers are balking to prescribe or cover these drugs (13). Price of Hepatitis C virus has been questioned.

In the United States, due to political influence, Medicare cannot negotiate prices. In many other countries, there are price controls and negotiated pricing with national healthcare purchasing. Pharma companies definitely do not like that. Generics love the high prices they can get for their products in the developed countries even after repeated product quality mishaps.

There is no question that innovation is needed in pharmaceuticals. However, the question is “are these innovations for the selected elite?”

Drugs are supposed to be beneficial for masses. However, with current drug prices, pharma companies while making profits are driving families to bankruptcies. High prices are definitely not giving pharma a good name. Is this the legacy pharmaceutical companies want? I do not believe so.  

It is my conjecture that for pharma to move from about 10-15 patients per million (=about 85,000 patients out of 7.2 billion global population) and high priced drugs to 7,000 patients per million or higher number (=about 5 million patients out of 7.2 billion) and affordable drugs, significant effort would be needed to discover drugs that are highly effective (no me-too) for common diseases. If such drugs are discovered they would also be an opportunity for significant manufacturing technology innovations.

Pharma (14) might achieve its projected $1.3 trillion sales in the next few years but it would have to pick its patient base. Would it be 10-15 patients per million, mostly in the developed countries or 7,000 patients per million worldwide? Do you think the later would happen?  

Girish Malhotra, PE
EPCOT International

1.     My Lunch With Shkreli: What We Should Learn From Pharma's Latest Monster: http://www.forbes.com/sites/matthewherper/2015/09/24/my-lunch-with-shkreli-what-we-should-learn-from-pharmas-latest-monster/ accessed September 26, 2015
2.     Turing to Cut Price of Drug Daraprim After Increase Sparks Outcry: http://www.wsj.com/articles/turing-to-cut-price-of-drug-daraprim-after-increase-sparks-outcry-1442970732 accessed September 26, 2015
3.     The Assault on Drug Innovation: http://www.wsj.com/articles/the-assault-on-drug-innovation-1442964103#livefyre-comment, accessed September 26, 2015
4.     New Weapon in Push to Lower U.S. Biotech Drug Prices: http://www.wsj.com/articles/new-weapon-in-push-to-lower-u-s-biotech-drug-prices-1442965627?tesla=y accessed September 26, 2015
5.     What Cancer Doctors Don’t Know About Cancer Drugs: http://www.wsj.com/articles/what-cancer-doctors-dont-know-about-cancer-drugs-1442961874 accessed September 26, 2015
6.     Biotech exec Martin Shkreli has history of tough tactics: https://www.bostonglobe.com/business/2015/09/25/how-martin-shkreli-biotech-pariah-put-cancer-patients-risk/fxjUV8alj28LESmmOF7IbO/story.html accessed September 26, 2015
7.     Lawmakers Seek Answers on Valeant’s Price Increases http://www.wsj.com/articles/congressional-democrats-seek-subpoena-of-valeant-over-drug-prices-1443468385 accessed September 29, 2015
8.     Drug Goes From $13.50 to $750 Overnight: http://www.bloomberg.com/news/videos/2015-09-21/why-turing-increased-price-of-daraprim-over-500- accessed September 26, 2015
9.     Bach, Peter M. Seeking a cure for drug-price insanity, Fortune Magazine http://fortune.com/2015/09/17/rising-drug-prices/ Accessed September 25, 2015
10.  Lupin diabetes drug price up by 200% in US http://www.business-standard.com/article/companies/lupin-diabetes-drug-price-up-by-200-in-us-115092400935_1.html accessed September 29, 2015
11.  Dishman to supply API for Janssen Pharma's TB drug Sirturo: http://www.business-standard.com/content/b2b-pharma/dishman-to-supply-api-for-janssen-pharma-s-tb-drug-sirturo-115092900626_1.html?src=email accessed September 29, 2015
12.  Gottlieb, Scott: A Clintonian Misdirection on Drug Prices, http://www.wsj.com/articles/a-clintonian-misdirection-on-drug-prices-1443568738 Accessed September 30, 2015
13.  Top U.S. doctors say pricey cholesterol drugs best for limited group: http://www.reuters.com/article/2015/09/24/us-usa-healthcare-cholesterol-idUSKCN0RO2DD20150924 accessed September 29, 2015

14.  Malhotra, Girish: Manufacturing technologies and their part, Chemica-Oggi-Chemistry Today, Vol. 33(5), pg.28-31, September/October 2015