Not to sound too “Twilight Zone,” but I would like to begin with…cue the background music:

“Picture if you will, a manufacturer of pharmaceutical poultices. As his equipment wears out, he chooses to replace it with the same units. He consciously replaces his equipment with essentially the same ones he has used since 1960. Prepare to enter…The Same-Old, Same-Old Zone.”

The question one must immediately ask is “why?”

When queried, the nervous man will stammer, “B-b-b-b-but the mean old QA man won’t let me change.” Or, “The mean old FDA (EMA – you pick one) doesn’t like change.” Or, and this is really the reason, “My people are familiar with model XYZ from Supplier ABC, so why change?”

Hence, when some pain-in-the-neck column writer suggests that a contract manufacturing organization (CMO) move into the light and try PAT, QbD, and, ta-da, continuous manufacturing, we hear a chorus of reasons why they can’t. Never underestimate the power of the Dark Side.

In previous columns, I have made the case for the economies of PAT/QbD, at least as far as attracting partners who are already using PAT for their blockbuster products in their own facilities. And, how process analyses can save time and money as well as attract new business. Expanding on this concept, I need to examine some truisms and observations:

1. All equipment wears out and becomes un-fixable. The third law of thermodynamics, loosely stated, is “Entropy, like Karma, is b---h.” All units will need to be replaced, at some point; some earlier than later.
2. Actually, very few equipment manufacturers either continue making the same models or have replacement parts for them indefinitely. Try finding an engine part for a 1971 Ford Pinto; worse yet, a 1972 Maverick.
3. The trends in modern process equipment are larger and faster. That means that classic batch processing formulation will need to be updated every time a larger mixer or faster tablet press is added to the line.
4. Classic formulation is seldom based on first principles or PAT or QbD. In all too many cases, scale-up may be described as hunt-and-peck. Doubling the size of a blender, for example, does not mean simply doubling the time for mixing. Without PAT-based materials’ knowledge, numerous test runs need to be made to make the new hardware produce a similar blend to the old unit. Plus, without in-line measuring technology, the new process would need to be stopped, have samples taken, have the samples analyzed in a lab, and only then can a new mixing SOP be written.
5. There is the capacity conundrum: if you stay small, you will need to turn down business, which hurts future contracts; if you expand with current batch-process equipment and do not increase business enough to fully utilize the equipment and personnel, you will squander the profits of the smaller contracts you now have.
6. Your clients are being squeezed for lower prices, so you will, in turn, be squeezed to lower production costs. So, increasing size, which has a number of hidden costs, can be a two-edged sword: both capacity AND overhead increase. Much like the addiction-spiral of blockbuster drugs, the success of selling more spurs you on to building for a larger capacity which, in turn, necessitates selling more product, and so on.

Now, I have always told my groups, it’s better to have too much work than not enough to keep your jobs. The trick in this case is that we do not have to choose between two options because there is a third: think small! After the inflation of Big Pharma by M&A for several decades, these companies are beginning to shrink. There is no one reason for this, but there is a perfect storm of conditions that are encouraging downsizing:

1. After a planned program of cross-validation, companies are able to produce whichever product they need at a multitude of sites. No longer do they need to have specialized plants for each blockbuster or “normal” product. This allows them to have fewer footprints, saving many millions of dollars, Euros, pounds, etc. each year. With the biggest-selling names coming off patent, this versatility is needed.
2. When the inevitable downsizing occurs, there is money to be made from divesting the equipment and properties of the unneeded plants. This is now the seed money for modernizing the remaining plants.
3. Even with the cost savings on brick and mortar and personnel, there can be loss of opportunity in off-patent, personalized meds, and orphan drugs, each of which takes up production bandwidth.

All these facts are all well and good, but what do they have to do with contract manufacturers? Well, let’s see. The industry has fewer sites, yet potentially more lots—albeit smaller lots—to produce. That means, using conventional old-time GMP batch-type processing equipment, even though the amount of product sold may be less and the profit margin slimmer, the work involved and warehouse space needed may not be significantly lowered. Why?

1. The cleaning of each piece and subsequent cleaning validation still takes approximately the same time. A thousand batches of any drug product, no matter how large the yield, will take pretty much as long.
2. If the over-flow or specialty products are contracted to CMOs while still being produced in the traditional manner, then they will suffer the same log-jam of too many products for too few process lines.
3. When a manufacturer makes a large number of different products, the logistics of quarantine and analysis of many more APIs more than makes up for the shorter run times of each individual lot.

So, despite a lower income flow, now we have potentially more numbers of lots and, even though smaller than during the heydays of their patent protection, the work involved remains nearly the same. Not the path to prosperity. Quite succinctly, replacing worn or broken equipment with like models does nothing to alleviate the blockage, save money, nor increase profits.

Since the FDA released the PAT Guidance (2004) and subsequent documents (ICH Q9-13), the industry in the U.S. and Europe has slowly been moving towards process monitoring (PAT) and Quality by Design (QbD). The former paradigm gives us the data needed to assure proper mixing, drying, and so forth, while the second is using the PAT-generated data to manufacture reproducible and quality products.

This is all well and good. The end product of a properly designed QbD program is, indeed, an excellent and reproducible product and no out-of-specification (OOS) batches. However, while the quality of the product may improve, simply making better batches doesn’t mean making more or faster batches. So, while employing PAT/QbD is a great idea, continuing to use conventional processing only give at best a 10-15% savings in time, which, in turn, barely makes a dent in the throughput crunch. What is needed is a different, 21st century solution.

A number of larger Pharma companies have bought into the idea of continuous manufacturing (CM) for several reasons:

1. A smaller footprint is, in itself, a cost savings.
2. Several of the companies have found that the contiguous units can be cleaned in-place. The conventional solvents, soap and water, followed by copious rinses and drying, then waiting for lab results keeps instruments out of use for large percentages of the available workday.
3. Scale-up times are avoided. When the small, experimental or clinical batch size is shown to be suitable for sale after NDA or ANDA approval, the exact same equipment is used for retail batches. They just run longer to produce more tablets or capsules.
4. Site validation becomes infinitely simpler. Pfizer has even gone so far as to produce a CM suite at a central location, validate it for use, then, via a tractor trailer, drive it to another site for use. The entire system need only be shown to produce the same product as when first assembled and, since it was never dissembled, can be put into use far sooner than previously for site validations.
5. Cost of scale needs to be considered. If most CM units are similar, then spare parts, maintenance, and training can be uniform. Since all the units will have nearly the same footprint, buildings will also be uniform. This, too, will lead to savings of building costs. You can use the same blueprints, if not the same construction firms.

So, with the spate of drugs becoming generic, specialty drugs (3-D printed, etc.), shrinking floor space of larger companies, and the increase of demand due in large part to aging populations, we have what may be referred to as an insurmountable opportunity. What is actually needed is for upper management to grow a spine. They simply need to ignore nay-sayers who are afraid to leave the mid-20th century and go for it.

Much as I like my uncle’s Studebaker, I drive a new Ford Fusion: spare parts are in abundance.

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Emil W. Ciurczak
DoraMaxx Consulting

Emil W. Ciurczak has worked in the pharmaceutical industry since 1970 for companies that include Ciba-Geigy, Sandoz, Berlex, Merck, and Purdue Pharma, where he specialized in performing method development on most types of analytical equipment. In 1983, he introduced NIR spectroscopy to pharmaceutical applications, and is generally credited as one of the first to use process analytical technologies (PAT) in drug manufacturing and development.