A Pharmaceutical Challenge for Technocrats

Pharmaceuticals have their own unique technology and pricing positions compared with the other chemical products. Can we introduce innovative development and manufacturing technologies for the pharmaceuticals sector? The answer in unequivocal ‘yes!’ We just need to understand the roadblocks and overcome them.

Since we want to live forever, we are willing to pay the demanded price for a drug. Our willingness to pay for long life along with the monopoly during the life of the patent has been the primary driver for setting drug pricing. Drug prices are set at the highest level the market will bear. Once the patent expires, brand companies move on to invent new drugs.

The above two factors ensure the desired profit margins for the pharmaceutical companies. Any costs due to regulatory mandate are passed on to the consumer. Thus, the need for product, process development and manufacturing technology innovation has been minimal. Inefficiencies are an accepted part of doing business. Generics have followed ethical (brand) companies in their modus operandi.

Regulatory bodies have cajoled pharmaceutical companies toward innovation by creating PAT, CMC, QBD and other TLAs. However, these cannot be forced or mandated unless some other event takes place, which will have a financial return. [We are familiar with the phrase “you can lead the horse to water but cannot make it drink.”]

There has to be a solution for this dilemma. Only an “economic incentive” will result in innovation.

Latent blame for the lack of innovation is placed on regulatory agencies. This is unjust. The repeatability of quality at the active pharma ingredients (API) and the final formulated drug stages is mandated- as it should be. However, the “path to quality” should not be mandated. Companies should be held responsible for “quality failure”. Penalty for quality failure has to be severe. Companies should have the freedom to choose the “path to quality” as it is the road to innovation and creativity.

Providing manufacturers with the freedom to choose their “path to quality” is the equivalent of stopping the sampling of intermediates” for quality. This will force everyone to “drink the water”. Companies will save significant money, which will be additional incentive for pharmaceutical development and manufacturing technology innovation.

Stopping intermediate sampling could be encouraged and even mandated. It will happen only if we understand “everything about the raw materials and intermediates but were afraid to ask.” I am quite confident that based on the education and training that chemical engineers and chemists receive they can become the proponents of “stopping the sampling of intermediates.” With their backing we will arrive at the destination where the regulators want us to go. Technology innovation is not hard and for the technocrats it is the most exhilarating experience.

We need to keep API and drug formulation as separate processes and that will simplify innovation. In general, many articles discuss pharmaceutical process improvements. These do not include API manufacturing process improvements but only refer to formulation process improvements. McKinsey in a recent report suggests that the pharmaceutical companies have an opportunity that exceeds about $65 billion through productivity improvements in the drug formulation area. Based on my review of the API segment, I believe that the opportunity in the API sector based on yield, technology improvements and conservation far exceeds $65 billion.

The question is: “Are the chemists and chemical engineers ready and willing to take the challenge?” I know the answer and it is “Yes we can”. If we do, many of the TLAs would become irrelevant.

Girish MALHOTRA, PE

President

Chemical Engineering: Understanding the Curriculum for Quality Manufacturing

Chemical Engineers during their training are taught that they will commercialize and/or operate a process that will produce consistent quality product all the time (without re-work) using a safe, sustainable and an economic process.

To achieve these objectives, we review topics that teach us the understanding of the physical properties of material (raw material, intermediate, by-product and the product) involved in the process. This allows us to understand their interaction in a reactive and/or a blending process. Chem. E. uses this information to commercialize a robust process.

If we have mastered the properties and the interaction of chemicals involved, we should be able to define the operating conditions of a process having the highest yield with above defined process characteristics. We are also taught various unit operations that we can use as is, modify and/or manipulate to produce a quality product all the time. If we are not able to achieve the objective of producing quality product using a safe and sustainable process, the first time and all the time, we have to improve our understanding so that we can have the correct process.

If I translate the Chem. E. training fundamentals to acronyms, we are taught to develop and commercialize a QUALITY BY DESIGN (QBD) process. This is our “hippocratic oath”. Anything short of this objective suggests that we need to improve.

Regulatory bodies have introduced few other acronyms in the pharmaceutical manufacturing. They are fine to have but what they mean and tell us is not totally understood. Interpretations of these vary and introduce variability. My question is: are we trying to have the best pharmaceutical manufacturing technology or are we trying to conform to the current fashion crowd?

My interpretation of QBA, CQA, CMC, DS, and PAT is as follows. If my understanding is not what the “guru’s” expect it to be, then please help with the correct interpretation.

• CQA [critical quality attributes]: We need to understand the physical properties of the materials (raw material, intermediate, by-product and the final product) and how they interact with each other.

• DS [design space]: Definition of the process operating parameters that have been identified by the developers, which if followed will produce quality product all the time.

• CMC [chemistry, manufacturing and controls]: Reaction mechanism, kinetics and process controls that is understood and followed will allow production of quality product.

• PAT [process analytical technologies]: This acronym is the least understood. It is believed that by having PAT, all of the process ills will go away. That is far from the truth. Analytical instruments will let the manufacturing and quality people know that the process has erred. However, it will not correct the problem and give a solution to the problem. Only people who are familiar with the characteristics of the materials and chemistry can correct the process. Analytical instruments are an indicator and not the corrector. There is difference between process control technologies and process analytical technologies.

• QBA [quality by analysis]: It suggests that we have a problem and we do not meet quality. We have to go back and fix the problem so that we can produce the desired quality.

To summarize the above mentioned acronyms are the fundamentals of chemical engineering curriculum. If we understand pieces parts of the curriculum, then we should have a QBD process. Question then arises why it is so hard to implement the fundamentals of chemical engineering in the manufacture of a pharmaceutical (API or a blend of API and excipients) or did I miss something.

Girish Malhotra, PE
President

Climate Change and its impact on Industrial Production

Climate change is a new challenge and a major discussion point between the developed and the developing countries. Some sort of emission limits will be placed as we move forward. There is lot of posturing and both sides are making point and counterpoint.

Developed countries did not have emission restrictions during their growth. With the current demand to curb emissions, some curbs will be negotiated. Developed and developing countries are afraid of the curtailment of their industrial machine. In order to retain their industrial complex developed countries will exert pressure. However, the developing countries especially India and China are not going to readily agree to any curbs. In Secretary Clinton’s recent trip India Rejected U.S. Proposal of Carbon Limits.

A recent article India and Climate Change takes India as example and excludes China, though both present similar challenges for the developed countries.

This article states “If (the) developed nations are held responsible for emissions that they historically contributed, oblivious to their impact on climate change, why shouldn't (the) developing nations take responsibility for producing generations of people who will generate emissions into the future?” Is it an indirect admission that the developed countries are afraid of the curbing their economic growth and are afraid of the growth of the developing countries? It seems to suggest that since the developed countries control their population, they can keep emitting at the current per capita rate. Is it also suggesting that the living standards of the developed countries should stay high and of the developing countries should not? If this is the latent intent, it is not going to sit well with the developing countries.

Are we saying “Maslow’s hierarchy of needs” only applicable to the developed countries? Developed countries have had the developing countries as their market, but now they challenging us on our turf, we are not willing to accept the challenge. The game has changed and we will have to play with the new rules. Their development and negotiation is going to be a challenge.

Recently International Council of Chemical Associations engaged McKinsey & Co. to suggest steps the chemical industry needs to take to curb emissions and still innovate. This study excludes chemicals that improve the living standards (including pharmaceuticals) and assumes gross savings from such chemicals to be zero.

I have concerns about this exclusion as we are excluding an important segment (pharmaceuticals about $800 billion revenue out of $3 trillion dollars per year) that has a large carbon imprint. Pharmaceuticals (API and formulated products) present an opportunity to reduce their imprint. There is an opportunity to improve their manufacturing inefficiencies (low yield) and reduce their solvent use, there by achieving an offsetting positive impact. Technology improvement will also reduce healthcare costs. An effort is needed in earnest.

Development and global sharing of the low carbon emission technologies might be the answer. Other choice for the companies in the developed countries is to move their factories to the developing countries. Thus they would not have to implement tougher emission standards. This is not a viable option.

In the last 15-20 years countries have become dependent on each other. What was environmentally acceptable yesterday will not be acceptable tomorrow. Since the global warming will affect us all, we will have to compromise and live with the new rules whatever they might be.

Girish Malhotra, PE
President