Continuous processes compared to any other manufacturing process have very unique characteristics. They have a stringent demand: Quality has to be built in the process from the start and it cannot be tested in. Some call the process quality by design, which is really an application of the fundamentals of chemistry—physical, analytical, inorganic and organic—and chemical engineering. These fundamentals have been applied in chemicals, coatings, petrochemicals and other allied industries. At times it seems pharmaceutical manufacturing has missed applying them and it is beyond my imagination. They should have been part of the process from time immemorial.
The important question is: Would the regulators and the industry hit the ground running when businesses change to continuous processes for the manufacture of active pharma ingredients and their formulations? We cannot overlook that the parts of the current regulations are batch-centric. Involved challenges would be worth the discussion. My concern is that the process would be easier said than done. I am sharing my perspective of the challenges and opportunities to produce quality product and maximize profits.
What makes a drug?
By definition each drug is a combination of active ingredients—fine/specialty chemicals that have a disease curing value—that is combined with inert excipients and chemicals, to create a dispensable dose. Dispensable dose could be a liquid, solid tablet/capsule or an ointment.
There is a reason and rationale for pharma’s current business model. It has done well to fulfill global healthcare needs and it might be useful to re-visit it. Brand/ethical pharma’s current model is based on discovering new treatments for an illness and commercialization after necessary testing and regulatory approval. Once the drug patent expires or is annulled, the drug generally becomes a generic and is produced by generic companies. The intent of brand/ethical companies is to extend patents as much as possible by whatever means possible. Brands essentially have no involvement in the drug once it becomes generic.
The volume of active ingredients needed to produce the formulated products dictates the manufacturing processes.
More than 90% of active ingredients are produced using batch processes. Formulations similarly are produced using batch processes.1,2,3 Since batch processes are and have been the accepted practice on the pharmaceutical landscape, regulations are centered around batch processing. Pharma batch processing is tradition-based because it is easier to commercialize rather than if it was science-based.4
Batch processes have fulfilled the prevailing need and the industry has done well in spite of its manufacturing and business inefficiencies. Asset utilization5 is less than par compared to other industries. Pharmaceuticals have tried to emulate practices of other industries in its supply chain practices but due to regulatory constraints, industry is challenged and has low inventory turns. It has to assure that every raw material is tested and sometimes even re-tested to assure product quality. The current practice of testing raw materials to assure they meet the specifications would have to be altered for continuous manufacturing. Regulations also require that the equipment is cleaned between batches and is at 100% performance. Since continuous processes have to operate 24x7x50 with allocated downtime, regulatory requirement of equipment cleaning will have to be reviewed. Start and stop process is not a continuous process.
The volume of active pharma ingredient needed to fulfill the product demand for the brand drug along with multiple producers of the same generic have essentially led to batch processes. The justification for this model boils down to availability, or being able to get a new brand drug from a single supplier. Generic drugs from multiple suppliers dilute the production volumes resulting in use of batch processes. This results in lack of economies of scale and not having the best manufacturing technology results in higher costs. All of these influences, compared to other industries, results in low inventory turns on the front and back end of the processes and cash flow is influenced. It has been said that multiple producers are needed to assure quality product supply. However, no one considers that inefficient manufacturing and repeated testing of in-process and finished products and low asset utilization can lead to shortages.
Continuous processes are defined by plants operating 24x7x50 hours with specified down time, which has benefits. Recently, few pharmaceutical companies have started to use continuous manufacturing but they do not elaborate on which segment of their operations—the active ingredient side or the formulation side. I conjecture continuous processing is being used in formulations only.
One question that has not been answered is the duration of time the process is producing a product. Based on product need, viability of 24x7x50 hour process could be difficult to justify.1,2
The fact that continuous manufacturing has appeared on pharmaceutical manufacturing turf is a major accomplishment for the industry that in general has been slow to adopt better, proven technologies. Excluding R&D, pharma has been a technology laggard in part due to its business model and prevailing regulations. Short patent life of brand/ethical drugs and regulations discourage manufacturing technology innovation. From a pharmaceutical company’s perspective 21CFR314.70 intervenes and discourages innovation after the products have been commercialized. Technology change is an expensive ritual even if any company wanted to innovate its manufacturing processes during its patent life.
Items that Need Attention
Once a new product has been successfully identified for clinical trials, necessary paper work has to be filed with FDA and other regulators. Since the commercial success of the product is not known, generally the active ingredient and formulation will be a batch process. Companies generally would not change their manufacturing process during clinical trials, and batch processing is most likely used to produce trial samples.
If a company decides to transition from batch to continuous processing, many of the following challenges would come in play. Dosage and commercial success determine the processes that will be used in future.1,2
- Review feasibility of continuous processes for the active ingredient as well as its formulation. It would involve defining the process operating 24x7x50 hours per year for the active and its formulation. Any different operation would be a deviation from the classical definition of continuous and should be explained and accordingly named.
- Develop the laboratory process with continuous process focus.
- Pilot plant and test the process for the product quality. Operating parameters are defined here but might have to be tweaked for repeatable quality product.
- Process design has to be extremely robust and repeatable such that the operating parameters and equipment do not alter the product quality.
- Can the company have its supply chain properly in tune to supply the necessary raw materials meeting its specifications and timing to assure that the process would not shut down?
- Can the company create/adhere to practices that exceed current regulations established by the FDA and other regulators? One has to be reminded that the current regulations are batch-centric.
- Companies will have to be mindful of any process changes/improvements in the manufacture of the active ingredient and their formulations, as what gets practiced on a pilot plant does not necessarily translate exactly to commercial-scale equipment.
- In-process samples can be taken but since the process is operating continuously, such samples will just indicate the state of the process. Robust process automation helps.
- Operating parameters have to stay within the predefined upper and lower control limits of the process operating parameters. If they are not, it is very likely that the product quality could be affected.
The process of manufacturing method differentiation and selection begins when the chemical molecule is identified. While developing most of the chemicals manufacturing processes—pharmaceuticals as stated earlier are chemicals in their active and formulated forms—it is not normal to start thinking about the kind of commercial process—batch or continuous—the product would have. Why is this so? The reason for this is very simple. Since product success is not known, most of the process development starts in the laboratory and generally it is a batch process.
Process development for batch and continuous have many similarities. However, there are significant differences, which mostly relate to how the available information is used, tamed and manipulated to create and commercialize great processes.
Each chemical, whether it be a raw material, an intermediate or a finished product has its own unique story and mutual behavior compare to the other chemicals in the mix. Everyone who is involved in the development and day-to-day operation learns and understands chemical and physical (social) behavior6,7,8,9,10,11,12 of involved components. It is up to a chemist and chemical engineer to recognize each behavioral nuance and exploit it to create an optimum batch or a continuous process. Creativity, imagination and familiarity with process equipment and cross-fertilization is helpful.
If the product becomes a commercial success, synthesis of the chemical and/or its formulation to a continuous process can be financially justified. However, conversion from a batch to a continuous process for the active pharmaceutical ingredient and its subsequent formulation is very different. Conversion to an alternate process would have to be done according to the prevailing regulations that dictate product efficacy and equivalency to the approved drug. With these stipulations it is not simple to convert an existing drug molecule and its formulation to a continuous process in totality or in parts.
Brand drugs under the current business and regulatory model have a lower probability for continuous processes especially for the active ingredient production1,2—formulations have a higher probability. If an active ingredient and its formulation need to be produced by continuous process, monitoring of raw materials and finished products will have to exceed every existing written regulation. Raw materials have to be perfect and within the defined limits. Also, traceability is very important. Deviation outside the defined limits could shut down the process and could impact product quality. There cannot be a wide spot in the process to hold material until the downstream equipment becomes available. Materials have to flow in and out in the allocated residence time.
Equipment cleaning as suggested by cGMP guidelines will have to be reviewed and modified if needed. In this discussion some points have been repeated to assure that we understand that the differences between batch and continuous process are significant.
Command and complete control of the process that will produce a repeatable quality product is a must. Process automation has to be extremely sophisticated and should make necessary process parameter adjustments to produce quality product with predefined limits. Mathematic models can be very helpful in designing a robust process. Finished products—active ingredient and finished dose—can be tested but have to be packaged in salable containers. These are challenges and can be met if things are thought through and done right. Benefits of the effort due to “first time quality” could be around 25-40%13 lower cost compared to a batch process.
There are other factors that add to higher profitability. High inventory turns, compared to today’s turns, improve cash flow. Better asset utilization can translate to larger market share and economies of scale can lower drug prices for the masses and generate higher profits.
Generics, based on product success, have a superior opportunity to capitalize on economies of scale to create better and more robust continuous or batch processes. Since generic companies know the molecule while the drug is under patent, they have ample time to create a process that is efficient, superior and can be commercialized after patent expiration. Principles of chemistry and chemical engineering that have been enumerated in textbooks can be easily applied for the manufacture of chemicals and their blends. Regulations that control drug manufacture cannot be overlooked.
If the product—either at the active or formulation stage—warrants a shift to continuous processing, companies will have to implement methods that exceed the current batch process-based regulations. Inventory management, product testing and supply will have to be re-evaluated and re-configured.
Since a continuous process is operating without interruptions, significant off-spec product could be produced if the process designers do not have total command of the processes. The downside of not having control and command of the process can be a high financial loss, especially for the finished dose. It might be possible to re-work the active ingredient to meet specs but most of the cost advantages could be lost.
We have to understand that the design demands of a continuous process are high and stringent but the benefits are also high. Going forward many companies will consider a 24x7x50 model with 85% operating time, or a 24x5x50 schedule with 85% operating time if the volumes are there. Such operations will alter the pharma landscape permanently. The possibilities of such happenings are more likely now than ever. Rationalization would still be needed and could result in a business model that is very different from the current model. Time will tell.
- Malhotra, Girish: Manufacturing technologies and their part, Chemica Oggi Chemistry- Today, September/October 2015 Vol. 33(5) pg. 28-31
- Malhotra, Girish: Continuous Process in Pharmaceutical Manufacturing: Considerations, Nuances and Challenges, Contract Pharma, June 2, 2015
- Malhotra, Girish: A Blueprint for Improved Pharma Competitiveness, Contract Pharma, Vol. 16, 7, Pg. 46-49, September 2014
- Malhotra, Girish: Why Fitting a Square Plug in a Round hole is Profitable for Pharma and Most Likely Will Stay? Profitability through Simplicity, August 1, 2014, accessed March 21, 2016
- Benchmarking Shows Need to Improve Uptime, Capacity Utilization, http://www.pharmamanufacturing.com/articles/2007/144/ accessed March 8, 2016
- Malhotra, Girish: Focus on Physical Properties To Improve Processes: Chemical Engineering, Vol. 119 No. 4 April 2012, pgs. 63-66
- Malhotra, Girish: Sociochemicalogy, www.pharmaevolution.com April 9, 2013
- Malhotra, Girish: QBD: Myth or Reality? Pharmaceutical Processing, February 2007, Pages 10-16
- Malhotra, Girish: Alphabet Shuffle: Moving From QbA to QbD - An Example of Continuous Processing, Pharmaceutical Processing, February 2009 pg 12-13
- Malhotra, Girish: Hesitation In The Drive To A Continuous Pharmaceutical Manufacturing Process: Real or Imaginary? Pharmaceutical Processing, July 2009 pg-12-15
- Malhotra, Girish: Review of Continuous Process for Modafinil, Continuous Processing in the Chemical and Pharmaceutical Industry II, 2009 AIChE Annual Meeting, November 10, 2009,Nashville, TN.
- Malhotra, Girish: Analysis of API (Omeprazole): My perspective, Poster Session: Pharmaceutical Engineering, 2009 AIChE Annual Meeting, November 11, 2009, Nashville, TN.
- Cost of Poor Quality, http://www.juran.com/elifeline/elifefiles/2009/09/Cost-of-Poor-Quality.ppt, accessed March 21, 2016
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. firstname.lastname@example.org; Tel: 216-223-8763