All opinions are my own.

Tuesday, November 28, 2017

Innovation In Pharmaceuticals: What Would It Take & Who is Responsible?

Humans from time immemorial through their imagination, creativity and different teachings have innovated in every aspect of life and things they have done. All of this should have happened for every aspect of pharmaceutical manufacturing also. However reading FDA’s PAT guidance (1) [excerpts shared below] one gets the regulatory perspective and their snap shot that suggests pharmaceutical manufacturing is trailing in innovation.

I have difficulties accepting their conjecture. We need to understand the basis and come up with a potential solution to remedy regulatory supposition. It will not be easy but we need to start a discussion. Sides will be taken and that would be healthy.

Unfortunately, the pharmaceutical industry generally has been hesitant to introduce innovative systems into the manufacturing sector for a number of reasons. One reason often cited is regulatory uncertainty, which may result from the perception that our existing regulatory system is rigid and unfavorable to the introduction of innovative systems. For example, many manufacturing procedures are treated as being frozen and many process changes are managed through regulatory submissions. In addition, other scientific and technical issues have been raised as possible reasons for this hesitancy. Nonetheless, industry's hesitancy to broadly embrace innovation in pharmaceutical manufacturing is undesirable from a public health perspective. Efficient pharmaceutical manufacturing is a critical part of an effective U.S. health care system. The health of our citizens (and animals in their care) depends on the availability of safe, effective, and affordable medicines.

Pharmaceutical manufacturing will need to employ innovation, cutting edge scientific and engineering knowledge, along with the best principles of quality management. Nonetheless, industry's hesitancy to broadly embrace innovation in pharmaceutical manufacturing is undesirable from a public health perspective. Manufacturers are encouraged to use the latest scientific advances in pharmaceutical manufacturing and technology.  
  1. Multivariate tools for design, data acquisition and analysis
  2. Process analyzers
  3. Process control tools
  4. Continuous improvement and knowledge management tools
Like medical doctors who take a Hippocratic Oath, chemists and chemical engineers a take an “invisible” oath and apply fundamentals of chemistry, chemical engineering, their imagination and creativity to best of their ability to develop, design, justify and commercialize pharmaceutical manufacturing processes that are ecofriendly and produce quality products first time and all the time. They are graduates of the same schools that have sent man on the moon and back and sent Voyager and Cassini. Thus we should not doubt their capabilities. Human instinct of continuous improvement always sets in after the processes have been successfully commercialized.

There is a latent conjecture in regulatory guidance that the chemists and chemical engineers have not done the best to create the existing processes. I have difficulty accepting regulatory perspective that pharma needs to innovate. Something is a miss some place.

Any layperson reading guidance excerpts would think that the API (Active Pharmacceutical Ingredients) and their formulation processes were designed by seat of the pants rather than by incorporating fundamentals of chemistry and chemical engineering. I hope that was never the case and is not the case even today.

Could it be that the regulations are standing in the way of continued pharmaceutical manufacturing technology improvement and innovation? PAT (1) guidance has few self-confessions in this regard when it suggests, “our existing regulatory system is rigid and unfavorable to the introduction of innovative systems.” Second clue from the guidance is “many manufacturing procedures are treated as being frozen and many process changes are managed through regulatory submissions”

There are few other clues, at least to me. 

1.     Regulators don’t trust company’s continuous process improvements and innovation for the existing processes on the belief that every improvement would change the product performance and its efficacy. Thus, the process has to be re-examined for product quality and performance. This admission could be a challenge.

2.     Many times chemists and chemical engineers see potential improvements only after the process has been commercial. In-house time and effort needed to prove equivalence, even if not necessary, along with paperwork needed to assure same product performance is either too expensive, cumbersome and not worth the effort as it takes too long to get the necessary regulatory approval. 

Suggestion of use of certain tools and methods mentioned in guidance is bothersome because without the use of these the basic design of a manufacturing process cannot be started. Thus, I am not sure of the rationale of the suggestion in the guidance.

Chemists and chemical engineers have the aspiration and take pride in designing processes that produces quality product from the get go. They have done this for as far back as time can tell. Quality by repeated analysis (QbA) (aggravation) has disastrous financial impact on the whole business process. One bad move can have catastrophic domino effect. It is Economics 101. Since it is being done in pharmaceutical manufacturing, it suggests that there are extraneous constraints forcing this scenario. If the business is highly profitable all ignored.    

Innovation in pharmaceutical manufacturing can only happen when the technocrats are given the freedom to innovate. However a qualification has to be attached to process improvements and that is the product quality and performance will not deviate from the approved product. With this freedom there should be string attached and that is if the performance is different from the approved product, company has to abandon the process change and if they don’t, the production has to be shut down. Only a financial constraint will be a deterrent to unscrupulous process innovation adventures. 

Reality is that the systems in place today are not conducive to pharmaceutical innovation once the processes have been commercialized. To change a process step, change has to be submitted for every product and can face the approval ordeal. Due to limited patent life brand products may not have the patent life for the change to come alive. Generics just do the best they can but then shy away for additional innovations for approval expense and delays.

If we want to have continuous innovation in pharmaceutical manufacturing then we need to change the current system. To change the current system regulatory bodies and the industry have to tango together. There has to be mutual trust from each side. Pharmaceutical manufacturing and regulatory product quality landscape will have to be re-sculptured.

Since better than 90% of the pharmaceuticals are produced by batch process, industry has become dependent on taking a sample almost after every step and check it for quality. Quality by analysis (aggravation) has become the norm even if the sample taken meets the specs. This has essentially established a culture and a business model that is very different from other manufacturing enterprises. Unlike other industries in pharma we see low inventory turns of raw materials, finished goods and intermediates. They require storage space and lead to poor use of assets. Whole business process is inefficient and cumbersome. Brigades vs. battalions are needed. Processes that are designed to produce quality product from the get go become victim of quality by aggravation process. Current business model has basically destroyed planned simplicity that works for every efficient manufacturing operation.  

I would ask another question to all associated with pharmaceuticals and that is “have we progressed with respect to innovations or are we progressing”. Most likely the answer is “no”. Regulators are telling the industry of what and how to innovate and the type of manufacturing process to use e.g. continuous processes (2). These are distractions. Regulatory abstinence of making suggestions on methods and types of processes that companies should use will have a very positive impact on pharmaceutical innovation.

I am not sure of the basis why the regulators are making suggestions of types of processes companies should use. Do they hands on experience in process development, design, scale-up, commercialization, justification and management experience in the manufacturing processes for products that are marketed? It takes significant rigor to make the suggestions.

Same wonderment also applies for many trade journal authors who postulate certain types of manufacturing processes for pharma. A process on paper is a speculation and is different from a lab process and miles apart from an actual commercial process. When rubber meets the road reality sinks in. My intent here is not to knit pick but face reality.

Industry knows and plays on its landscape. They know and need to justify every investment of new process technologies and every improvement. As suggested earlier, regulatory bodies need to facilitate these innovations and investments by reducing the approval time. As suggested earlier manufacturing process suggestions made by the regulators are a distraction. Most of the process methods and technologies have been existed and are used in industries other than pharma. My conjecture is lack of financial justification in the current business model along with regulations has prevented use of such processes and innovation.

If regulators want industry to innovation then they have to have a defined road map (3) that companies can follow for process and quality approval. Regulators need not know the process design and operating parameters. However, companies have to document every change. There has to be a time period in which companies can expect approval of their submission. Regulators have laid out the cGMP practices that companies have to follow. In a previous blog I suggested three months for generic ANDAs (4). New brand drug manufacturing approval process of 18 months or less could be a target. Such expectations will present challenges for the regulators. There has to be a trust established and if the trust is violated shutting down of the operation has to be the only recourse. 
Regulatory bodies should layout the expectations for every new product specifications in a certain specified time and let the innovators innovate. This will help and lower drug commercialization time.

Lack of trust and re-checking the checker seems to be the problem also. Such situations develop only when the deliverables change from the defined specifications because someone dropped the ball. Trust has to be earned and cannot be taken for granted. Any deviation from expected specifications and processes as suggested earlier should have strict penalty like closure of the facility with no “ifs and buts”.

To recap it is in the best interest of the industry to innovate and it should be allowed to continuously improve their existing processes even after the regulators have approved the produced products and as long as the expected deliverable quality is not compromised. Review of improvements made after initial approval should be on faith, trust and desire. If regulators find excursions outside the strictly defined boundary conditions, such operations should be shut down. Only strict financial constraint will keep everyone on their tows.  

Process of continuous improvement/innovation (5) will make drugs affordable and improve pharma revenue and profits. I just wonder why pharmaceutical industry shies away from win-win opportunities. Inaction suggests that the current business model needs change.

Girish Malhotra, PE
EPCOT International

1.     Guidance for Industry PAT—A Frame work for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance http://academy.gmp-compliance.org/guidemgr/files/PAT-FDA-6419FNL.PDF
2.     Malhotra, Girish: Batch, Continuous or "Fake/False" Continuous Processes in Pharmaceutical Manufacturing, Profitability through Simplicity, July 20, 2017
3.     Malhotra, Girish: ANDA (Abbreviated New Drug Application) / NDA (New Drug Applications) Filing Simplification: Road Maps are a Must, Profitability through Simplicity, May 11, 2017
4.     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
5.   Malhotra, Girish: An Alternate Look at the Pharmaceutical World and drug affordability, Prospects, Analysis and Trends in Global Pharma, CPhI Annual Industry Report 2017, page 36-41, Accessed November 28, 2017

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