Greetings, friends. When last we spoke, we discussed some non-traditional methods for integrating new materials into our process stream using R&D technologies. I do, after all have a cacoethes scribendi (an insatiable urge to write), so I shall explain what other technologies would aid in making a better product over and over.

Light-Induced Fluorescence

Initially called LASER-induced, LASERs were replaced when they were found to both burn excipients (namely lactose) and degrade active pharmaceutical ingredients (APIs). The basic theory behind this technology is that, using the proper wavelength and intensity of light, any organic molecule (preferably the API) can be induced to fluoresce. This was first used to monitor blend uniformity in real time. Since companies have been performing this analysis since 1990 with near-infrared spectroscopy (NIRS), you might ask why use another technique?

I have always pointed out that NIRS, based on physics, is not a trace-material method. For mixes of powders (typical Pharma granulation), it is preferred that the analyte have a minimum not much lower than a few tenths of a percent. Since most traditional formulations ranged from the ~5% (typical) to 50% (Tramadol) to 75% for Tylenol to 99+% for aspirin, this hasn’t been a problem.

Yes, birth control tablets were in the less than 1% range, but these were the exception—until the newer, more potent drugs began to come to market. These were not a friend to NIRS, but, since fluorescence is more sensitive then NIRS, it was used for these components. Figure 1 shows a lab batch-blending of a Salmeterol mixing into a Lactose medium. While the lactose has a small background fluorescence, it is constant and allows the monitoring of the API addition(s) as they blend evenly.


Later work has been performed where the LIF beam is mounted on the tablet press and is used to monitor the uniformity of individual tablets, as they are being made. Figure 2 shows how such a set-up may be mounted, while Figure 3 shows how the signal is proportional to the compression force on the tablet granulation. This allows both control of the API levels and as a check of the continuity of compression, from each pair of dies.

Robotics (automation, really)

This concept is very broad and covers many “automated” functions, both static and mobile. Some examples of 21st century money-saving ideas are:

1. Raw Material Labeling. The biggest time-crunch that I have seen is in handling raw materials. Ignoring the ultimate solution of qualifying them, as they are delivered, via a portable NIR spectrometer, this is the next best idea. Big Box stores have an ongoing problem: comparison shopping via iPhone. As the customer walks along the merchandise shelves, he/she can compare the posted prices with other stores’ list prices.

The store manager can have his people change the posted prices, but that takes people and time. By the time a current price is listed, they could have lost numerous sales. Several years ago, a solution was discovered—the labels were changed out for, what was in effect, mini-iPads. These receive-only 3”–5” screens could be changed instantly from the manager’s office. The current price is then the displayed price in real time without printing new labels, without a dozen employees running around the store.

Why is this good for us? Currently, a lot of raw material is delivered—for argument’s sake, say 225 containers of lactose—transported to the quarantine area and labeled as “being tested.” Samples taken to QC, tests run and the lot is sent back (or destroyed) or approved. In any case, new labels are printed, affixed to each container and the materials moved to the appropriate area of the warehouse. Time, effort and storage space is burned.

It is (NOW) possible to scan the bar code on each container (they all have them) and the screens under them display the lot number, chemical name, date received and condition of analysis in red or yellow until approved. When the results of the QC assays are received, the SCREENS are changed, instantly and automatically, from the QC office. The materials need not be moved, as their location and analysis condition are clearly displayed. This alone saves an immense amount of time and energy.

However, as they say on TV commercials, “Wait. There’s more.”

2. Raw Materials Retrieval. Since we know where (row, rack, level), what (identity: name and lot #), and analysis condition (received, in process, approved, or failed) of all our raw materials (or in-process materials), we can now go “full-on Amazon.” What is full-on Amazon?

Quite simply stated, this is the warehouse model of the future for any company that stores many containers of multiple materials. In these warehouses, robotic units are sent to retrieve the materials for an order, which is then delivered to the operator’s station to be placed into a shipping container. In our case, this could simply be a robotic helper bringing the prober number of green-tagged raw materials to the proper room in production.

The robots are programmed to move to the proper location, a RFID signal from the screen below the raw material acknowledges lot number, ID and approval rating of this material. The proper amount is taken off the shelves, the data logged—so we know immediately whether we have enough for the next X number of batches scheduled—and taken to the proper manufacturing suite.

An added benefit would also be that we could use the oldest lots first (operators may not always check), choose lots by water content, if that is critical, and any other number of benefits. All automatically. We could even use these data, coupled with upcoming production schedules to order replacement materials—like supermarkets have been doing for 25 years.

3. Routine, Repetitive Chores. Much of a modern (post-1960s) production facility has very clever automation. A number of bottles are filled simultaneously with the proper tablets, labels are affixed mechanically, cotton balls inserted and caps screwed on, all by mechanical means. There are still a large number of chores that are performed manually.

Visual examination for defects of tablets/capsules by a number of staff, as they are produced, is slowly being replaced by machine vision devices. This could be sped up. Packaging materials are still located on warehouse shelves, hand-loaded on carts and delivered to the packaging room. These steps could be approached as the powder raw materials in previous steps 1 and 2.

4. API Synthesis. While not currently the bailiwick of most contract manufacturing organizations (CMOs) or contract research organizations (CROs), the current world political situation bodes poorly for generic drug production. The two major sources for APIs are India and China in that order, despite most people thinking China is our largest supplier. These two account for almost all the actives we use, with India having over 100 production facilities.

With the current dispute(s) with Russia, oil and gas are not our only problematic imports. Both India and China have increased purchases from Russia and have shown little taste for working with the U.S. on sanctions. In fact, the supplies of APIs may well be kept internally before being exported in the future, as both countries increase their national healthcare systems. In addition, the sterility and other problems with Indian facilities is not a minor problem.

I would suggest that major (generic) actives could be competitively produced in-country (largely because of labor costs) if the synthesis is aided by automation (PAT/QbD) and AI oversight.

As an afternote, a number of robotics suppliers are leasing and renting them—with instruction and applications support—to companies who either cannot afford them or are not convinced to spend the funds on “unproven” technologies. I encourage all the above solutions, so I can have faith in my next prescription being inexpensive and safer. 

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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. For more information: emil@ciurczak.com; www.thenirprof.com