With the multi-country, multi-suppliers, multi-distributers, and multi-thousands of miles long supply chains we have in the Pharma industry, security is a very real problem. Of course, it is a problem in all industries, although only a few may be considered critical/essential. It may only be an inconvenience if your shoddy hair clippers break, but it could well be critical if “knock-off” bolts, used in a passenger plane, suddenly fail. You may not care if your Beanie-Baby is a cheap counterfeit, but you should care whether your blood pressure meds are real or cheap counterfeits. What is the answer?
 
In order to assure quality and proper meds being dispensed, the EMA (European Medicines Authority) published a document (guidance/rule) entitled the Falsified Medicines Directive (FMD). This ruling was supposed to be in effect in 2019, but many delays have occurred, in no small part due to COVID-19. Substandard or counterfeit products is not a minor problem. An estimated 1 in 10 medical products circulating in low- and middle-income countries is either substandard or falsified, according to new research from WHO. Since 2013, WHO has received 1500 reports of cases of substandard or falsified products.
 
Of these, anti-malarial drugs and antibiotics are the most commonly reported. Most (42%) come from the WHO African Region, 21% from the WHO Region of the Americas, and 21% from the WHO European Region. This is likely just a small fraction of the total problem and many cases may be going unreported. For example, only 8% of reports of substandard or falsified products to WHO came from the WHO Western Pacific Region, 6% from the WHO Eastern Mediterranean Region, and just 2% from the WHO South-East Asia Region. Prior to 2013, there was no global reporting of this information. Since WHO established the Global Surveillance and Monitoring System for substandard and falsified products, many countries are now active in reporting suspicious medicines, vaccines and medical devices. WHO trained 550 regulators from 141 countries to detect and respond to this issue; as more people are trained, more cases will be reported.
 
This is all well and good, but what can be done to ensure proper products are being dispensed to patients? We have two major types of dosage forms to consider: injectables and solids. Let’s address injectables first.
 
Injectable meds come in two major forms: 1) Single or multi-dose vials and 2) pre-filled syringes. The first are the “old, dependable systems” and the second form represents a relatively new product. Pre-filled syringes are excellent in emergency or operating room settings and can be lifesavers where time is a factor. The newer application comes into effect in home-care or adult living facilities. In these “other” settings (especially considering the aging population), medications often need to be given (routinely) by caretakers, not always medical staff. The way laws are written, a nurse or doctor has to be the one to fill a syringe from a reservoir for injection. However, when pre-filled syringes (with proper drug and volume) are used, anyone may assist in administration.
 
While both forms are subject to FDA requirements of assay and stability testing, a clear, colorless liquid is not as easily distinguished as color and numerically coded tablets/capsules. A quick test before filling vials or syringes (especially for compounding pharmacies, who generally do not have labs for testing) would help supply chain/id/purity testing. One potential instrument is currently being sold.
 
The Dynalabs DVx is a compact, multifunctional UV-Vis spectrometer¹ with software that allows it to identify and quantify pharmaceutical liquids in seconds. This device can improve compounding quality and minimizes potential drug diversion, and improves patient safety. The first application is fairly obvious, since filling multiple clear liquids at a single facility can lead to mix-ups. The diversion feature is important since, as I have mention before, some countries allow drugs to be returned to central distribution points before expiry dates. Since the warehouses have no labs, controlled substances could be substituted with water.
 
In a similar situation, when prefilled syringes are withdrawn from a hospital pharmacy, unused units cannot be returned to storage (in the U.S., at least) and must be destroyed. The unused, say morphine, could be replaced by water for destruction and the drugs diverted or even used by healthcare personnel. The device only used a few microliters, so even the syringes used for the patient could be checked before use.
 
Techniques such as NIR and Raman Spectroscopy have been proposed to identify solid dosage forms.² It was considered a good proposal, since it has been successfully used for clinical samples and is currently used in real-time release testing (QbD/CM) at many locations. At one point, I was in favor of this approach until reality “slapped me upside the head.” As I look at the actual logistics, several serious flaws struck me:
 
1. A single product (e.g., Atenolol) may have several strengths, multiple producers, and multiple production sites. The data-base for this one product would be a chore: it would need to be checked vs. other looking tablets, production sites, and all current and future manufacturers.
 
Now, multiply the amount of work (time and money and materials) by all the solid dosage forms on the market and you begin to see the logistical problem.
 
2. In order to have the pharmacy (private or hospital) check the drugs, they would need an instrument (as well as access to the database). Ok, which instrument? NIR? Raman? Whose? Using a spectral database for all the products—we cannot expect a pharmacy to have multiple instruments and multiple databases—assumes one type. How do we propose choosing and building enough instruments in a timely manner?
 
3. Which group/agency would secure all the disparate products, scan them, and generate the needed Chemometric equations/databases?
 
Even though I liked this approach (15-20 years ago), I began to despair that it would ever happen. One day, I was awaiting a flight in the Zurich airport and was chatting with a fellow at the airport pub. His company sold larger (meaning expensive) equipment and he was in charge of stopping counterfeiting/diversion. Their approach was a holographic image on the shrink wrapping on the units.
 
I liked the idea of “tagging” shrink wrap, but holographic imprinting is too expensive and complicated for millions of smaller bottles/blister packs. I observed a candy bar and the packaging gave me an idea. The bar code on every individual container (now in 2-D for more information) can contain a plethora of information: date of manufacture, location of manufacture, product ID, etc. Since the “Tylenol scare,” decades back, the majority of individual consumer products have shrink-wrap as a safety measure. These two ubiquitous components gave me an idea: combine the two in some way as a security/identification system.
 
The idea was to embed the shrink wrap with (up to six) small, stable molecules that could be detected by NIR, Raman, or even Visible spectrometers.³ The wrap could contain any number of these selected chemicals (not in contact with the product), not necessarily all of them. The approach would have several positive attributes:
 
1. Since the materials would only have to be present or absent, a quantitative equation is unnecessary. Any NIR or Raman could be used, avoiding being forced to use a single supplier’s instrument.
 
2. Once shrink wrap has been shrunk, it cannot be re-used, avoiding reusing it after substitution of the product.
 
3. If the end user does not know the sequence in which the materials are measured, giving us 720 combinations to arrange/read the six. Only using some and representing “present” with a “1” and “not present” with a “0,” the result is a binary number, e.g., 100110. BUT, the customer/pharmacist does not know the order in which they should be placed, so the same six results could be 111000 or 000111, etc. The only “key” to the order resides at the place of origin (the cloud?) and a scan of the barcode, accompanied by the spectral readings will result in a “safe” or “not secure” response from the mainframe.
 
4. The order of the component readings could be randomly changed since there could be 720 unique combinations, making that set good for several years.
 
5. Even if potential counterfeiters/thieves discover the identities of the trace chemicals, they can be switched out for new materials and the code started over.
 
As with any new idea, there are always some flies in the ointment. Remember when it was “common knowledge” that a train, going over 50 mph, would kill passengers because they couldn’t breathe at that speed? And airplanes? Never work, they said. When presented to several pharma companies, the answers were (sadly) as expected:
 
1. It can’t work (number one response).
2. Sounds good, let me know when someone else begins to use it.
3. Even though it costs pennies (on products that are worth many dollars), no one wanted to pay for the safety. Some suggested they might use it if the government or public body covered the costs.
 
Obviously, we are not going to solve all counterfeiting and diversion problems with a single solution. We need a full quiver of tools—to quote Scotty on Star Trek, “The right tool for the right job.”
 
References
1. Contact: Stephen Kukielski, DVx Product Manager, +1 314.371.6435, 2327 Chouteau Ave. Saint Louis, MO 63103, DYNALABS.us
2. “A General Test Method for the Development, Validation, and Routine Use of Disposable Near-Infrared Libraries”, J. Near Infrared Spectroscopy 9, 165-184 (2001) Co-authors: C. Tso, G. Ritchie, L. Gehrlein
3. U.S. Provisional 61/454,854 (2011): “Handheld Multisource Fusion with SmartWrap and Layered Verification Options” OPLF Ref #: FLAN.P-004-PV

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Emil W. Ciurczak is president of Doramaxx Consulting. He 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.