Some of the newer drugs are extremely potent, allowing for lower level dosage forms—often in the <<1% API range—to be administered. From a patient’s standpoint, this means lowered side effects, smaller dosage forms that are easier to swallow for geriatric patients and children, and possibly lower costs. Producing the dosage forms comes with a new set of parameters.

Since it is summer, I will start with the good news. First, with lowered doses, the overall number and volume of excipients are also lower, allowing smaller equipment to be used. When using less material, less space in the warehouse is needed. Fewer shipments of excipients also means fewer samples for QC to assay. Also, smaller tablets/capsules require smaller containers, meaning lower shipping costs and less warehouse storage space for finished products.

Unfortunately, there are also a few downsides to potent, mini-doses. Being more potent, and potentially hazardous, than normal drugs, the handling—weighing, transporting, adding to blenders, sampling, and so forth—may need be done with breathing apparatus, gloves, and gown. This is not to imply that any API is totally harmless, but inhaling small amounts of or touching something like acetaminophen is hardly life threatening. This adds time and expense and potential liability issues arise.

In addition, cleaning and validation thereof can be tricky with extremely low dose products. If we have an SOP stating that “less than one dose may remain on X-cm2 of surface,” then the onus is on proper sampling and extremely sensitive analytical methods to remain in compliance. Microgram residual levels of API could, theoretically, put the equipment out of compliance.

Lastly, if the API, as with many newer actives, is poorly soluble and needs to be in an amorphous form to be bioavailable, spectroscopic methods for determining crystalline form are strained by extremely low levels of material. After-the-fact analysis will prevent an OOS product from delivery, but not be of much use for control of production.
At this point, I will point out that, in any group in which I had a voice, we referred to the above and insurmountable opportunities. I am fond of stating, “If it were easy, you wouldn’t need a consultant.” Without trivializing any of the above downsides, many, if not all, could be addressed by a well-designed PAT/QbD system and, better yet, by a continuous manufacturing system.

Starting with the so-called simplest part of the production process, weighing, we need to address the two potential points of concern: toxicity and accuracy. Without dwelling on physiology, it should be evident that, if the dose is very small, the chemical/biological activity of the API is enhanced. As the dose moves from, say, 25-100 mg per tablet to, perhaps, one 10-25 micrograms per dose, it is rather simple math to see that the drug could be as much as 10,000 times as potent as the typical material handled in production.
This could mean mandatory safety precautions well in excess of “normal,” including full “monkey suit” and breathing apparatus. This costs time and money as well as potential hazards for the operators. Also, without implying anything negative, plant operators are not analytical chemists. Weighing kilo-sized portions is far simpler than weighing gram-sized portions. The chance of sub or super-potent final products is enhanced by the far smaller mass of API needed to be weight and carefully transferred to the mixing apparatus.

The precise amount needed for the product is added with mechanical accuracy in a CM process, eliminating most errors in high or low doses. The fact that the API is in an enclosed vessel also protects operators, aside from the initial loading of the bin, from exposure to the drug. Two potential problems, solved with one device.

Content uniformity can be a more difficult target to “hit” with miniscule dosage levels, as well. Physically, the number of particles of excipient so greatly outnumber the particles of API that any minor heterogeneity is amplified. The “good enough” approach for larger doses (10-50% w/w) is not good enough for a case where the number of particles of drug may almost be counted in the tablet/capsule. Just a small amount of API, either high or low, could lead to super- or sub-potent doses. Again, traditional methods of testing—stopping the blender, using a sample thief, sending samples to QC, waiting, then deciding to pass or fail—may not be sufficient for low dose products. More samples may need to be taken and analyzed to assure homogeneity, although, as a physical chemist, I know powders cannot truly be homogeneous, just well-blended.

This is a case where the current in-process (PAT) “standby,” near-infrared spectroscopy (NRS), may not suffice. The acknowledged lower level of NIRS is roughly 1% API. That would leave LIF (Light-Induced Fluorescence) as the technology of choice. Briefly, LIF (where the “L” was originally for LASER) is a very simple concept: a bright beam of light, a laser-diode or SLED (super-luminescent light-emitting diode), is shone on the powder mix, causing the complex organics (the API, in this case) to fluoresce. As the blending proceeds, the level of fluorescence is measured and when the levels are constant, the mix is declared complete.

Since fluorescence is a very sensitive technique, it has been routinely used in lieu of NIR for years when the API level approached 1% or below. While many of the units are non-specific, very little of the blend, aside from the API, fluoresce. By contrast, NIR and Raman can see all organics and some multivariate equation is needed to see only the API during the blending. This makes the calculation of the end-point of the blend rather simple: without fancy, complicated and potentially time-consuming to validate math, the signal merely needs to level out, within predetermined limits, and the blending is complete. Of course, as with any step in a GMP-compliant process, this will need to be validated with compendial technology (e.g., HPLC).

Cleaning the production machinery is never fun, simple, or obvious. The operator in charge of cleaning needs to be sure that all the water-soluble and water-insoluble components are removed from the surfaces of the equipment. The process usually involves multiple steps, involving solvents, detergents, and purified water. Then, someone needs to swab the surface with appropriate solvents, attempting to determine that there is little to no material remaining. The spec for cleanliness is some level of dose, perhaps less than one unit dose, over a set area (often 10 cm²), determined buy some analytical method. While merely time-consuming for larger doses, the aforementioned very small dose levels make the process quite difficult.

Two alternatives may be employed to make the low dose cleaning faster and more effective. First, for a batch process—either classic GMP or PAT controlled—the manual swabbing of the equipment could be followed by use of an Ion Mobility (IM) unit. This device, a later version of the ones found at airports, works by vaporizing the materials removed from the surface of the equipment, giving them an electrical charge, and running them through a column to a detector. The principle is much like a time-of-flight mass spectrometer, but does not require a vacuum or fancy software.

The components of the wash solution acquire a single charge and travel along the tube, arriving by increasing molecular weight. The recorded signal resembles a chromatograph, where the arrival time gives the molecular mass and the signal strength gives the amount present. The entire analysis takes roughly 20 milliseconds.

In addition to being faster and possibly more accurate than the standard “sample and sent to the lab” approach, the operator knows, within seconds, whether he/she needs to perform further cleaning or that the unit can be placed back into service immediately. This step, alone, increases the availability of process equipment, cutting back on the need for more hardware on hand.

The second way to assure cleanliness is achieved in a continuous manufacturing set-up. After the product has been completed, a common excipient—salt, lactose, or microcrystalline cellulose—is run through the system until clean as per validation. The subsequent product blend excipient blend may then be used to clean out the cleaning powder, prior to initiating the actual product blend.

This benefit also obviates the need for the operator who does the cleaning to take precautions, such as mask, gloves, and even full covering for highly toxic drugs. In addition, this does away with the dismantling of the CM unit and the washing step, again, allowing the unit to be used in short order, cutting the needed inventory of process lines.

As for the last difficulty, morphology, there is one possible solution for measuring in real time: time-gated Raman. Overall both Raman and NIR are very good for determining polymorphic forms of API and excipients, such as sugars. However, we have already established that the level of API makes NIR problematic and, at lower levels, normal Raman’s fluorescence background makes it a poor choice for analysis. In a previous column, I showcased a product where the LASER that strikes the sample is pulsed nanosecond bursts and the emitted light is samples in picosecond time frames, allowing the Raman spectrum to be enhanced. This would be a good tool to try for determining the polymorphic state of the API, especially is it needed to be amorphous for solubility’s sake.

So, it appears that a number of answers to problems in analysis or procedure not only make handling and analysis possible, but they speed up and help with the quality of the product, itself. And, for an added bonus, they free up the process equipment more rapidly for subsequent batches. Win-win-win, I would say.

---

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.