There is a saying in the business world: “You need to spend money to make money.” If you couple this with, “Don’t bring a knife to a gunfight,” you have the beginnings of a path to success for the Pharma manufacturing “guild.” From the largest multi-nationals to the “mom and pop” generics and contract sites, if you spend enough in your lab update/start-up, you will get the best bang for your bucks.

Continuing with dusty bromides, our industry can be “penny-wise, but pound foolish.” Ignoring the fact that some companies spend more on marketing than R&D, we are mandated by law to analyze incoming raw materials (excipients, packaging materials, and APIs), intermediate steps (generics need to monitor blending for every lot) and finished products. This takes personnel, lab equipment (and glassware and chemicals), and lots of lab space. Whether you have a world-class or so-so lab is not a lot of dollars or euros different.

“Wait!” you might say, “the cost of a ‘world-class’ lab from ‘barely tolerable’ one could be a few hundred percent.” True, if you only bought the equipment, placed the people in the lab, and never touched anything or tried to do an analysis, it would, indeed, be a needless expense. However, while this tableau may make a nice photo for a trade magazine, it doesn’t work for a commercial (working) endeavor.

In the real world, many, many samples are generated in production, often at a rapid rate, sent to the lab, prioritized, prepped, analyzed, and results sent to the proper venue (QA, production, etc.) This is where the “worth” versus “price” becomes clear. Price and worth are not the same: think priceless vs. worthless. For example, look at a routine HPLC. The difference between, say, 5 minutes vs. 15 minutes for a result (same sample prep for both, etc.) may not seem much, but I have worked in labs where we made 40-50 lots of the same product, every week! Now, assume the mandated 10-20 units of finished product for each lot, and we have 400 to 1000 HPLC samples of a single product, weekly!

Now, for the 15-minute elution time, we have 6,000 to 15,000 minutes of elution time versus 2,000 to 5,000 minutes. Assume a flow rate of between 1-1.5 mL/min and we have 6,000 mL to 22,500 mL of solvent (6 to 22.5 liters of solvent per week for one product). The cost of doing business, you say? I used to think so, too, until I was introduced to UPLC (very high pressure, low flow) chromatography,

A few years ago, at one client’s location, while I was waiting for a service rep to perform an IQ/OQ (instrument quality, operational quality) on an NIR (on which I was to do method development), I sauntered to their QC lab, looking for something to do. Their main (virtually only) product analysis method was HPLC: 1.5mL/min for 16 minutes. For those of you slow at math, that’s 24 mL of solvent for each sample injection. Over a year, for a small company, this is both a time-killer and major expense.

Using their UPLC (fortunately, they had the same packing as the validated method), I switched the method to 0.6 mL/min for 6 minutes—3.6 mL per injection vs. 24 mL per injection. For 20 samples (one lot), that means 72 mL versus 480 mL per lot! Again, for the math-challenged, that’s 12 minutes for UPLC vs. 320 min (5.3 hours!) waiting for results to pass/fail the batch. Of course, I am ignoring sample prep time, which is for another day.

I haven’t mentioned the cost of solvents, yet. It costs to buy them, store them, and legally dispose of them, which often costs more than original purchase price. Using the above example and setting the price for the organic component at let’s say $50 per 4-liter bottle, 20 lots would cost 0.5 liters (UPLC) vs. 9.6 liters (HPLC). That is, one product line, in one week, can use $25 worth of solvent vs. $480 worth. When one considers a moderately large company, the time and cost really adds up quickly. This is not even considering the size of inventory needed to store and possible hazards in storing and moving larger amounts of toxic, flammable solvents.

Another area that is a “black hole” for time and personnel is cleaning validation. One of the major driving forces for PAT/QbD is the large percentage of manufacturing equipment not in service at any given time.

Depending on the company and product diversity, there may be almost 80 percent of a company’s equipment just sitting, waiting to be cleaned, cleaned and waiting for testing, waiting for test results, and so forth. The most popular (I use that word ironically) method is to swab various positions throughout the unit and send the swabs to the QC lab to be analyzed. We addressed the time involved in the example above.

There is always the possibility of proceeding under risk and assuming the equipment was clean, but, since I am assuming honorable companies are reading this, I will suggest a faster, easier way to test for residues. As seen in your local airport and used by TSA to check for explosives, Ion Mobility Spectroscopy is a rapid and specific method to check for residue(s). Simply stated, IMS is a small pseudo mass spectrometer. Figure 1 shows a schematic of an IMS. The sample is placed at the input area, the materials are ionized (radio isotope or electron passage), passes through a grid (ion gate) of the same charge (+ or -) which accelerates it down the column (drift region) to an ion detector. Since each molecule is given the same charge and each has a different mass, the ions move down the drift region in the order of reverse molecular weight. That is, lighter molecules “elute” before more massive ones (see Figure 2).

If the UPLC vs. HPLC was a massive time-saver, the jump from even UPLC (3-8 minutes) to IMS (10-30 milliseconds!) is exponentially greater. Going a step farther, in the past few years, IMS has been used (either alone or linked with MS) as a primary analytical technique. Table 1 shows a comparison between IMS and gas chromatography, liquid chromatography, and capillary electrophoresis. Figure 3 shows IMS used in place of an HPLC. Regio-isomers are separated in under 20 msec. If better resolution is needed, an attached mass spectrometer may be used for better resolution.



This is one of many techniques waiting to be fully utilized. As Nike says, “Just do it!” So, welcome to the 21st century, fellow Pharma travelers. Tune in next month for more time, money, and space savers.