Sometimes the answer to a question exists and while everyone is aware of the answer, it can be ignored for convenience’s sake. However, it is good to ask the question again to refresh and reinforce the existing and established answer. We all know the answer to the question, “Who is responsible for the product quality and manufacturing process technology innovation for any product?” The answer to this question has been in front of us since the Stone Age. It is, of course, the manufacturer and manufacturing process developer who is the creator of the product. Other entities can, and do, assist in the process. But, I am revisiting the question and the answer to ensure that we all are on the same page. It is my perspective and not intended to question the creativity and imagination of any individual or entity.

Since the Stone Age humans have innovated and created products and processes that improve life and lifestyle. Time after time human creativity and imagination has delivered and transformed our understanding from the Stone age, through the Industrial Age and into the Information Age. Remarkable contributions to human progress have been made. As products and processes developed over time, innovators also realized that every useful product and/or process may or may not be safe for the consumers and workers. However, over time product quality, consistency and process safety factors gained importance. Since many products impact human life, regulatory bodies were created to safeguard consistent product quality, integrity and safety. They achieve this by using robust and reliable processes, and as a result product quality consistency became critical for the survival of businesses. Regulatory bodies were also created to assure environmental preservation for generations.

Product producers even with the best processes and product quality at times live at the edge to maximize their profits. This is true for most enterprises. This is not a bad thing, so long as producers can maintain product quality, their safety and profits.

If we focus on the chemical industry, which includes pharmaceuticals as a subset, the manufacturing philosophy is to maximize profits while retaining product quality and safety. This is economics 101 and the basic building block of every business. Competitive pressures keep companies on their toes for product quality and safety through manufacturing process technology innovations and continuous improvements. Again, every manufacturing technology innovation has to come from the product manufacturing organization.^1,2 In addition, their incorporation in every process has to be justified. Companies have to make sure that they do not run afoul of the regulatory requirements. If they do, they deserve to be penalized with no exceptions.

Predictions warn that in the next few years we will lose valuable process advances if regulators do not stop dictating approaches. We are seeing pharma companies whose goal is only to meet regulations, which leaves companies devoid of innovating process advancements. Maybe, if given the freedom by forward thinking pharma companies, contract development and manufacturing organizations (CDMOs) may have the incentives to innovate new process and manufacturing improvements and be a key part of the solution. I’m hopeful that if the regulators are listening, over the next few years they will create a positive environment where manufacturing technology innovation can occur by shortening approval time to three months. This way commercial and financial considerations can dictate innovations—continuous manufacturing is an ongoing case in point.

Below we discuss the entities that participate in making sure that each manufacturing process and product follow certain norms.

Process developers, designers and commercializers
Chemical synthesis process design and formulation depends on product demand. Generally, manufacturing processes fall into two categories—batch or continuous. Their definitions are well established^3,4 and have been accepted for over two hundred years. Chemists and chemical engineers manipulate chemical synthesis steps, unit processes and unit operations, to create an economically viable process. The same thing happens for formulations. Understanding and exploiting physical and chemical properties of chemicals plays a significant role in process development, design and commercial operations.⁴ 

Creativity and imagination play a significant part in selection/manipulation of unit processes and unit operations in development, design and commercialization of an innovative and economic process. The resulting innovations can many a time stump even the equipment manufacturers. They, after justification, may be incorporated in the manufacture and formulation of chemicals. Each process, especially continuous processes, are chemistry, formulation and demand specific. Thus, the philosophy of batch processes, that many products fit the same equipment, does not apply to continuous processes.  

During the design of a pharmaceutical process and/or product, like in any chemical synthesis or formulation process, chemists and engineers are assigned the task of creating the most economically viable process that produces quality products from the beginning using safe processes and practices. Actually, instead of being assigned, it is expected they will create and commercialize such processes. They follow what is normally taught in their curriculum and hands-on training. If the commercialized process does not produce quality product the first time, it suggests all of the necessary process design considerations have not been incorporated in the process. Every “t” has not been crossed and every “i” has not been dotted. It could point to a lack of experience and also suggest short comings in their education. If the expected norms are followed, product quality is built in rather than tested in. Harsh words, but shortcomings ultimately lower profits.

However, if an external enterprise suggests and/or tells a manufacturing enterprise that it has to build quality in their products, the manufacturing organization is essentially being told that it has failed to do what is expected of them, which is to design and produce quality products from the start. With this lack of a quality culture, the long-term viability of enterprises can be jeopardized. By having outside guidances/directives on process design, quality and manufacturing methods or technologies, I believe our universities are also being indirectly told that they have failed to teach process developers and designers the value of innovation and creativity in process design.  

As stated earlier, product demand and volume dictates the type of process (batch or continuous) that will be used. Investment and profits of the company depend on the process selected. Each process type has its own established definitions.^3,4 One cannot and should not ignore these established definitions and misrepresent realities. In addition, one should not, and cannot, create their own definitions to suit their objectives. 

Since the discussion and use of continuous process pharmaceuticals has become the latest fantasy, it is necessary to acknowledge and differentiate between a batch and a continuous process. Batch processes operate part time during the 8,760 hours that are available per year. Batch campaigns can be done multiple times during the year to satisfy the product(s) demand if the demand is not large enough to operate 8,760 hours per year. A continuous process⁵ means an 8,760 hours per year production of a single product with minimal or no downtime. Downtime means the time when the product is not being produced. It includes time for preventive maintenance, generally pre-designated, or time due to fix un-expected process upsets.

Ironically, many drug formulations have the demand to be produced using continuous processes but the producers have opted not to do so. The reasons and rationale for not doing so are not known. Could it be internal reluctance or tradition? My conjecture is that it is a combination of both. The majority of active pharmaceutical ingredients (APIs), except for less than ten, are produced using batch processes even if they could be produced using a continuous process.

Equipment supplier and CDMO
My definition of equipment supplier is much broader than the generally accepted definition. I have included the contract developer manufacturer (CDMO) and the equipment supplier in the same category. My basis is that each is a vendor that loans or sells their equipment to a company that needs to produce a product. In addition, a CDMO can facilitate process development as discussed earlier.

Equipment suppliers provide relevant machineries for different unit processes and unit operations that are used in a batch or a continuous chemical synthesis or formulation process. Each innovates equipment and associated process methodologies to gain an edge over competitors. The process developer (client) has to be sold on the efficacy of the equipment or the process. Process economics plays a vital part in equipment/process selection. Financial justification has to be made by the client. It is to be noted that the same processing equipment can be used in a batch or a continuous process. Determination of how the equipment is used is made by the process developer/designer and is based on product demand and is not made by the vendor or the regulator.  

A contract manufacturing organization (CMO) uses the client company’s process and fits it in their equipment to produce the desired quality product. CMO personnel can be a facilitator and innovator, but they still have to sell their innovations to the product developer. Again, everything has to have financial justification. 

Regulators
It is my understanding that the primary task of the regulators is to assure consistent and repeatable quality product is available independent of the type of manufacturing process used, or for that matter, any and every manufacturing process. Regulators have established cGMP practice guidelines that need to be followed. They have the obligation to approve the manufacturing process and the final product rather than endorse any type of manufacturing method. As indicated earlier, process selection and product quality assurance are the responsibility of the manufacturing company.

The regulator’s endorsement, or suggestion, of the type of processes/methods that should be used, in my estimation, is unethical. It is tantamount to favoritism for a type of process and is synonymous to interference in the manufacturing company’s decision-making process or the equipment supplier’s business. It is also, as stated earlier, questioning the competence of chemistry and chemical engineering curriculums at our universities who have trained the best of the best worldwide. If the chemists and chemical engineers at the companies are not continuously creative then our universities and companies have not trained them adequately and our educational institutions, as well as the companies, have not crafted an environment for continuous innovations and improvements.

FDA’s recent blog⁶ gives the impression that investing in continuous processes will lower costs and produce quality products. This could happen if the process meets the demand and operating criterion outlined earlier. Each continuous process design and equipment configuration are product and demand specific. The blog does not recognize that unlike batch process equipment where many products can be produced in the same equipment, continuous process design cannot be used to produce other products unless the chemical synthesis and formulation needs are exactly the same or are similar. This is a critical differentiation and on that is not understood by the blog author. 

Regulators, as well as the product producer, developer and equipment supplier, cannot change science-based established definitions without due process and public review, which applies to creating new or changing established definitions. Lately this has been done without any explanation. 

Since the regulatory bodies are making suggestions about the “how and what” of manufacturing processes, a question needs to be asked. “Are these suggestions/recommendations being made by the personnel with actual hands on experience in process development, design, commercialization and operations of chemical or pharmaceutical plants that produce salable products? Have they justified such investments?” If they have not, I would question the credibility and authenticity of their suggestions.

I would also like to ask the regulators how much effort they have made to simplify the drug filing and approval processes, which could immensely lower approval filing costs.⁷ I believe some effort has been proposed recently, but how long it will take to become a reality is anyone’s guess. 

More than ten years ago regulatory bodies suggested that the companies should move from Quality by Analysis (QbA) to Quality by Design (QbD). Companies should have questioned this suggestion as QbD is the basic building platform for every commercial process. It is ironic that many companies diverted significant attention to this suggestion as if they were not practicing QbD. It is well accepted that to produce a quality product every company has to have repeatable command of the process, which is QbD. My conjecture is that significant monies have been spent by the companies to follow QbD practices. It could have been better spent elsewhere. Did the companies get any return on the monies spent? Most likely none.

Such regulatory suggestions are like telling a master chef how to slice and dice onions when he/she practices the art to perfection every day. Since quality issues still persist, my conjecture is that the companies still do not have absolute command of the processes or are not following good manufacturing practices. It is interesting to note that with QbD fervor fading and another fervor—continuous manufacturing—is taking hold. In order for continuous manufacturing to take place, it needs to meet the established definition and has to be economically justified. Continuous manufacturing in pharmaceuticals is a long way from reality.⁸  

How manufacturing technology innovation can become routine?
Brand and generic pharmaceutical companies, due to a combination of short patent life after new drug discovery, long regulatory approval times and their ability to secure the demanded selling prices, have no desire or incentive to innovate manufacturing technologies. They believe and practice well-known and best processes and methods to manufacture their products.

CMOs, CDMOs and equipment manufacturers have a significant manufacturing role in manufacturing technology and method innovation. However, the adoption of these has to be financially justified. 

Regulators have to create a manufacturing technology innovation environment. One of the ways I see that happening is to shorten approval time to three months. This will give companies the freedom and the incentive to innovate and compete on cost while maintaining quality, which will allow them to capture bigger market share. They will also be able to achieve have higher profits. Drug affordability will improve and shortages could drop also. In addition, regulators have to stop suggesting which methods and processes companies should use. Companies, as stated earlier, have to justify their investment on the basis of product demand, a fundamental of every business.

I also believe that companies are lost in excessive regulatory guidances and directives that are a distraction. Regulators are suggesting manufacturing companies to practice continuous improvements for what they practice. The question that needs to be asked to the regulators is if they are practicing continuous improvements also. If they are, costs and time associated with dealing with regulators could be significantly lowered.

Regulators will resist giving companies the freedom that would come with short approval times. They still have ultimate control being able to shutter manufacturing facilities if quality deviations exist and cGMP practices are not followed.⁹ Loss of profits alone should be enough incentive to maintain quality and follow good manufacturing practices. 

References

1. Malhotra, Girish: Innovation in Pharmaceuticals: What Would It Take & Who is Responsible? Profitability through Simplicity, November 28, 2017 Accessed July 10, 2018
2. Malhotra, Girish: Pharmaceutical Manufacturing Technology Innovation: Does Reading the Tea Leaves Matter? Profitability through Simplicity, December 22, 2017 Accessed July 15, 2018
3. Batch Production, https://en.wikipedia.org/wiki/Batch_production, Accessed June 20, 2018
4. Continuous Production, https://en.wikipedia.org/wiki/Continuous_production, Accessed June 20, 2018
5. Malhotra, Girish: Chemical Process Simplification: Improving Productivity and Sustainability John Wiley & Sons, February 2011
6. Gottlieb, M.D. Dr. Scott,  FDA Budget Matters: Investing in Advanced Domestic Manufacturing, FDA Voice, July 13, 2018 Accessed July 13, 2018
7. 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 Accessed July 10, 2018
8. Malhotra, Girish: The Good, The Bad, The Ugly (1) Complexities of Pharmaceutical Manufacturing, Profitability through Simplicity, April 9, 2018 accessed July 10, 2018
9. When E.F. Hutton talks, people listen. https://www.youtube.com/watch?v=wd7gC_IZmMM Accessed July 18, 2018

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Girish Malhotra
Contributing Editor

Girish Malhotra, president and founder of EPCOT International, has more than 45 years of industrial experience in pharmaceuticals, specialty, custom, fine chemicals, coatings, resins and polymers, additives in manufacturing, process and technology development and business development. girish@epcotint.com; Tel: 216-223-8763.