As if to emphasize my prior comments on supply chain difficulties, the war in Ukraine has added to the problems caused by COVID. Namely, auto makers in Europe are stalled by lack of parts from Ukraine, adding to the bottleneck of computer chip and nickel (used for batteries in cars) shortages. Also, since the planting season begins in April, there is a chance that as much as 30% of the world’s wheat supply is in jeopardy. This highlights the need for even more streamlined production and ability to switch from traditional suppliers to new suppliers in a short time period.

As I suggested last month, the best solution to a 15,000-mile supply chain is to drastically shorten it. Also called “on-shoring,” finding alternate sources of raw materials and equipment closer to home is an important first step. Granted, we are not just looking for a replacement for lumber, simple hardware or chemicals for dishwasher detergent. The requirements for pharmaceutical ingredients are far stricter.

We not only need to consider chemical purity and sterility, but the physical properties needed to produce a product with current Critical Quality Attributes (CQAs). These are the weight, flowability, compressibility and most importantly, the reproducibility of bioavailability when compared with the ANDA or NDA submission (and clinical trials). That means we need, to some measure, to go back to “square one.” That is, we may well need to use measurement tools normally associated with preformulation and formulation research.

Don’t panic, let me explain! When we compare the costs of qualifying new vendors to building more warehouses and storing millions of dollars of in-process materials, you will see that a short supply chain and local vendors is a more fiscally responsible solution. A number of technologies are used in the original manufacturing process development of a dosage form. When the “ideal” form is produced and filed in an NDA or ANDA, the raw material suppliers are, in essence, fixed.

While the original intent of PAT Guidance (Process Analytical Technologies) was to assure more reproducible product, with an added benefit of money savings—fewer in-process and final product tests—it can now be used as a screening process for substitute materials that can be used to give the desired end product. The key paradigm change in PAT/QbD versus “traditional GMP” is the agency-approved ability to modify a process in real time versus having to adhere to fixed and immutable conditions (e.g., “blend for 20 minutes at 15 rpm” morphs to “blend until minimum variation is seen over time”).

In the simplest of terms, this eliminates most of the “traditional” in-process tests (e.g., disintegration, hardness, etc.) that are limited to a few tablets per hour and substitutes tests capable of large numbers of meaningful tests in nearly real time (e.g., NIRS, Raman, TeraHertz spectroscopies). The former (under GMP) is often referred to as “test to quality” while the latter is “design for quality.” In other words, plan A is “make the product; test the product; sell or destroy the product.” Plan B is “control each step in real time, allowing continuous monitoring and changes, to consistently generate a quality product.” Plan B seldom, if ever, includes failing the final product. In simple terms, a six-step process—weigh, blend, granulate, lubricate, tablet, coat—cannot proceed from step “1” to step “2” unless “1” passes quality standards. “Step 2” to “step 3,” “3” to “4” and so on all have the same restrictions. Thus, the final product has passed all QC tests already, so a final release test is redundant.

The benefit of manufacturing under 21st century conditions (PAT/QbD) is that substitute raw materials (new or alternate vendors, due to supply restrictions) can be given abbreviated tests (sterility, ID, purity) and the potential physical differences from original sources can be accommodated in the process via process changes, based on real-time measurements. That would mean, for example, slight particle size distribution differences can be overcome by changing times and speeds of mixing. In other words, the new, flexible process can be continuously adapted to any physical variations between raw material sources.

One useful tool, previously seen as pure R&D, is Electrical Impedance Tomography (EIT), a vessel (from a dissolution flask to an industrial-sized blender; powder or liquid types) is equipped with numerous electrodes encircling the outer wall. Figure 1 shows an example of EIT showing the dissolution of a tablet (USP standard paddle set-up). This technology highlights the effectiveness of the apparatus and where the solution should be sampled. Figure 2 shows the efficiency, and time needed to achieve homogeneity, of mixing an added liquid aliquot to a powder blend.

The technology may also be used to equip the feed onto a tablet or capsule frame, allowing the operator to check for smooth flow. Any void would show up on the read-out. Short-term, this may be addressed by shaking or tapping the point(s) of voiding. Long-term, the knowledge might lead to a design change or addition of some vibrator for the problem products.

This can be a once-in-a-while approach when testing a new vendor or grade of excipient for the first few batches of product. Even if you decide to remain with GMP batch production, you could modify the process times or measurement techniques to the new materials, then set the SOPs accordingly. Adjusting the depth of sampling of a dissolution should not be considered a “change” per se and shouldn’t trigger any QA actions beyond, perhaps, a mention in the end-of-year report.

Another technique that sounds “exotic” but, unlike most other spectroscopic techniques requires minimum calibration is LIBS (LASER-Induced Breakdown Spectroscopy). The instrument uses a fine LASER to pulse the surface of a sample, causing it to vaporize. As this plasma emits light based on the elements present, the spectrometer portion identifies which elements are present. Of course, as with any spectroscopic technology, the more of an analyte present, the larger the signal. Figure 3 shows the basic schematic for a LIBS unit. The LASER pulses repeatedly with each pulse burning slightly deeper into the sample.


If this is a coated tablet, for example, the spectral intensity (and whether it is present or absent) of elements in the coating (Fe, Ti, etc.) can be seen and the amount estimated. This fingerprint, based on a number of points across the surface of the tablet, shows the efficacy of coating, thickness of each point along the surface, etc.  In other words, how effective is the coating process. This allows for adjustments in time and coating procedures for any particular process, showing potential changes needed when evaluating new suppliers.

As the LASER penetrates the actual core tablet, the pulses begin to show the distribution of materials within the tablet, too. Figure 4 shows the differentiation of calcium stearate and magnesium stearate. These data show 1) the type lubricant used, 2) the relative amounts, and 3) the distribution throughout the matrix. Obviously, this technique could be used as a “quick and dirty” test on granulation before pressing and tablet cores, pre-coating. The granulation test would show whether the granulation passes specs and whether or not to continue the blending or proceed to tableting. The distribution within a core determines whether to proceed to coating or not.


While earlier versions of the LIBS technology were primarily for metals, newer versions are used for non-metallic elements as well. Nitrogen, sulfur, carbon, fluorine, chlorine and oxygen are most often tested. Figure 5 shows a “spectrum” of Furosemide with carbon, oxygen, sulfur and nitrogen highlighted. These spectra may be used to 1) show the correct API is present, 2) the distribution is nominal, and 3) with some calibration, concentrations may be determined. While not a compendial substitute for HPLC or NIRS, the speed of the test may be used as an indicator for the first several tablets off the press, allowing for adjustments to me made before the supply of granulation is expended.


There exist many tools, either applied in development or not common, at all in the industry that may be applied as interim quality assessments in place of traditional tests. The ability to rapidly and, in some cases, non-destructively test materials while in production instead of post-production is a time and money saver.

The next column will highlight some other methods for testing stability of new excipients in current formulations and fast methodologies for evaluating so-called “same as” materials from different vendors.

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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