By Emil W. Ciurczak, Doramaxx Consulting
Many years ago, while I was a high school science teacher, I was addressing some young people at a science fair. I did not go with a set agenda but instead wanted to field questions about science. One youngster asked about robots and when they would be coming (this was 20+ years ago). I outlined what a robot does, in simplest terms: It 1) performs a simple operation, over and over, 2) without constant intervention, and 3) needs occasional calibration. When I asked what would qualify, only one young lady raiser her hand “A clock,” she stated. Indeed, she nailed it.
She saw that, no matter how complicated a machine becomes, each part only performs a simple task. A gear rotates, a spring slowly uncoils, the hands (independently) move at a constant rate, and so on. In physics, any complex motion may be broken down to any single point in the motion, where its X, Y, and Z vectors can be measured. The entire waveform, no matter how complex, is merely a summation of these simple points. In a pharmaceutical example, the process of assembling a dosage form is a series of very simple machinations — weighing, pouring, mixing, wetting, drying, sieving, tableting, and coating may all be broken down into very simple motions.
Thus, whether the tablet is made over several weeks/months or in minutes, the actual physical steps are the same You finish one step, stop, store, test, and then move to new location, repeating the process until the product is complete. Any differences in time scales are due to the intervention of operators and physical movement of the in-process materials from step-to-step.
Adding continuous monitoring and connecting the steps in a single location enables a process known as “continuous manufacturing (CM).” Well-known in almost every other manufacturing industry, CM was only very recently adopted in the pharma and biopharma industries. Companies who have begun using CM have enjoyed (overall) success, making product faster and with virtually no rejects. By eliminating the scale-up step, CM can save as much as six months from development to full-scale production, brings products to market faster.
The question is no longer, “Will continuous manufacturing work?”, but “When will everyone be doing it?” There are still many objections, including (but not limited to):
As my father told me, “If you don’t want to do something, you will find an excuse; if you want to do something, you will find a way.” Indeed, we have industry “experts” who declare that pharma and biopharma can’t do process analytical technology (PAT), quality by design (QbD), or CM because, no matter how quickly the process steps are enhanced, it will always be a batch-driven technology.
The “pharmaceuticals can’t be done this way” crowd seems to miss the crux of the matter: While laundry detergent earns manufacturers pennies per gallon in profit, (top selling) drugs can command dollars to thousands of dollars per tablet. There has been far less financial impetus for pharmaceutical manufacturers to streamline the process, when compared with consumer products. There have always been dozens of laundry detergents on the market, and they lack the patent protection pf a new drug entity (NDE). The sole provider of a patented drug can charge whatever they wish without any incentive to economize the production process. In short, no one does anything unless they feel a need, but for the pharmaceutical industry, that need may be coming soon. Facing an aging population and many products coming off patent, Pfizer, like many established pharma giants, is reshaping its organizational structure. At the beginning of its 2019 fiscal year, Pfizer will be divided into three businesses: Innovative Medicines (biosimilars and a new hospital medicines business for anti-infectives and sterile injectables), Established Medicines (to include generics and older branded drugs like Lipitor that have lost patent protection), and Consumer Healthcare (for over-the-counter medicines). This industry-wide trend places production costs under a new microscope. With international competition (especially from countries with far lower labor costs), many nations imposing pricing restrictions, and the cost of R&D not becoming lower, simply raising prices is no longer a viable option.
Drug makers are also outsourcing much of their work as they shrink to “virtual” companies, concentrating on R&D. They are using contract manufacturers for packaging, distribution, manufacturing off-patent products (to compete with generic houses), and even some research. As the supply-chain — everything from raw materials through delivery to pharmacies and hospitals — stretches over thousands of miles and dozens of countries, the crux of the problem can be distilled to one word: quality.
When our industry began as a commercial enterprise (around World War II), it moved from the back rooms of pharmacies to factories. The regulations, as is the case for any innovation, lagged behind). When a neighborhood pharmacist made a lot of 50 to 100 pills or capsules, “quality” merely meant using proper materials and accurate weights. The earliest production facilities could only manufacture product in the thousands, so the U.S. Pharmacopeia (USP) suggestions for analysis were deemed sufficient. In reality, compendial tests are almost entirely for identity (is it lactose?), purity (heavy metals, moisture), and final assay (originally titrations, now chromatography). Sixty to seventy years ago, the original compendial tests assumed that:
The supply chain was also very different then and has changed in several ways:
So, how can we assure product quality and consistency from country to country? Well, the first attempt was to introduce the FDA PAT draft guidance in 2002 (and final in 2004). Its purposes were to:
With PAT in place, manufacturers had control and a hard copy of data proving they were in control throughout the process. The fine-tuned FDA PAT guidance concerned quality by design (QbD), where known and/or unexpected variation in raw materials and intermediate products were anticipated and the effect on the final product was known. This allowed operators to make changes to the process (the collective gasp you just heard was from the old-school QA people reading this article) to assure compliance with known acceptable product parameters.
At this point, we had the tools necessary to assure that a product being made in France is (essentially) the same as in the U.S. or Poland or Malaysia, with a paper-trail to show how the process proceeded. As new, rapid, reliable monitoring tools became available, pure economics dictated where materials were purchased or fabricated. Now that spectrometric methods can assure similarity or equivalence of materials, we simply need to assure that the final products are equivalent.
We work under the assumption that, with guidelines from International Council for Harmonisation (ICH), FDA, and EMA for the calibration, validation, and application of spectrometers in pharmaceuticals, performing an analysis in Thailand will yield the same results as would be seen in Switzerland. What has not been standardized, however, are finished product analytical methodology and in-process controls. Let us assume for a moment (I am blindly optimistic here) that all jurisdictions suddenly homogenize finished product specifications. Then we can work on making the same product at every location.
How? Continuous manufacturing. When you are monitoring every material (from weigh-additions to final dosage weight) at every step and using those data to control every step, there is a pretty good chance that the product from country/location A will be almost identical to that from country/location B.
For the small minority of readers who are not familiar with CM, the process takes place in a multi-story facility, where the raw materials (API and excipients) start out in dispensing hoppers. These are dispensed by weight/gravity into a blending apparatus, often a screw-type blender. This blender has (at least) one monitoring point, normally for a near-infrared (NIR) spectroscopy fiber probe. Further blending (as with a lubricant), drying, etc. is also monitored by NIR, Raman spectroscopy, etc. The tablets are monitored, as is any coating process.
The beauty of this technology is multi-faceted:
In closing, I will paraphrase my financial guru (Jack Carroll): “You don’t have to use PAT, QbD, or CM; neither do you have to remain in business.”
This article has been adapted from the 2018 CPhI Annual Report.
About The Author:
Emil Ciurczak has advanced degrees in chemistry from Rutgers University and Seton Hall University. He has worked in the pharmaceutical industry since 1970. In 1983, he introduced near infrared (NIR) spectroscopy consulting for Technicon (Bran & Leubbe), NIRSystems (FOSS), CDI Pharma, Infrared Fiber Systems, Brimrose, and Buchi. Most of his research was on pharmaceutical applications of NIR, about which he has published over 40 articles in refereed journals and over 200 magazine columns, and has presented over 200 technical papers.