I got involved in packaging for my first full-time Pharma job (CIBA, 1970) for the purpose of integrating the “new-fangled” concept of plastics: plastic bottles and blister packaging. I was a simple physical chemist who asked a lot of questions. From the viewpoint of a newly minted chemist, the equipment and freedom I was given, made it seem as if I woke up in Heaven. To repay them, I quickly destroyed one of the most popular forms of samples given to physicians, namely strip-packaging. For those of you who don’t remember strip-packs, they were single dosage forms, sealed in cellophane, rolled, and distributed in a box, designed to be torn off and given as samples.

Using moisture transmission, oxygen transmission, and other tests, my findings showed that tissue paper would have protected the samples as well as the plain cellophane. A quick inquiry disclosed that adding a moisture/oxygen barrier as a coating and the new machinery needed to fill the strips would make the packaging more expensive than the drugs it contained. The economics forced us to investigate blister packs—a new and untested methodology.

The other bold new idea was to use plastic bottles in lieu of glass containers. The immediate savings in weight/shipping/breakage were apparent. The mechanics were less obvious. For example, the filling of the bottles needed to be modified. Plastic is more elastic than glass, so the first tablets dropped into the bottle bounced differently than into glass bottles, causing more interactions between doses, causing an increased number of cracked/broken tablets. The shape of the bottle, speed of fill, outline of the shoulders, and the materials from which they are fabricated affect filling mechanics.

The ubiquitous silica gel packs, now in every bottle, only became necessary because plastic is unique. When you tighten the cap, no matter how hard, the material “creeps” and the cap becomes loose. If you go to an old cathedral in Europe and examine the windows, you will notice the bottoms are thicker than the tops; glass, a super-cooled liquid, flows, as does plastic. In addition, “pure” polyethylene (PE; all polymers have anti-oxidants, etc.), without colors or light-blocking materials, allows most light to strike the product. The solution was to add titanium dioxide (TiO2); but, how much? We tried 1-5% and did the measurements. In this case, more is not better. It was much like the three bears: 1 and 2% were insufficient, 4 and 5% undermined the structural integrity of the polymer, and 3% was just right. Of course, we still had reservations. We did parallel stability studies in brown glass, just in case plastic didn’t work.

On top of all these physical “difficulties,” there was the chemistry to consider. I believe that Thimerosal, popular in the 1970s in nose drops, was not taken out of cold medicine or vaccines due to concerns about mercury, but concerns that the plastic dropper and/or bottle quickly absorbed the bacteriostatic material, allowing bacteria to flourish. Nevertheless, there are compelling reasons to substitute plastic for glass: safety, cost, and convenience.

Now that all this work was done on the actual packaging, the equipment that dispenses the tablets/capsules from bulk into bottles needed to be redesigned. The speed of delivery and angle of entry is different from dispensing into glass bottles. The tack-seal and capping machines needed to be modified, as well as all the labelling chemistry and application on the containers. Basically, the cost savings came at a cost.

Despite all of the time, R&D, and monies spent on the new paradigm, there were too many lawsuits over mislabeled products. J&J had a serious number of recalls a few years ago for mislabeled products. In plain language, that means the wrong product is placed into a bottle and shipped. Another mix-up occurred when birth control tablets were placed into dispensers incorrectly. For anyone unfamiliar with the modus operando of a typical prescription for birth control tablets, the package, round or rectangular, has both active and placebo tablets. The placebos are “place-keepers,” allowing the woman to take a tablet daily and not have to constantly check a calendar to see when to begin or end taking the active tablets. While the placebos are usually different colored than the actives, a tinted plastic container, and human inattention, might cover the fact that the tablets are out of order.
In one case, just a few years back, a woman in nursing school became pregnant while taking her birth control medicine. The active/placebo sequence was incorrect, so she was, in effect, not protected. She had to drop out of school and had no insurance. The company producing the drug paid millions in a lawsuit settlement.

The case I am making is that, even under the strictest cGMP environment, even using PAT/QbD, even in a continuous manufacturing line, the weakest link in the “chain of custody” is when bulk dosage forms arrive at the packaging line. The dosage forms, either for clinical or commercial release, arrive in fiber or plastic drums with identifying labels attached. The bulk material(s) are then distributed to packaging lines and filled into blisters or bottles. In all cases, the packaging line is dependent on the label(s) on the bulk product arriving from production.

I have personally received materials when in R&D from production that were mislabeled. Human error is human error and, until only androids work in industry, incorrectly labelled materials will arrive on the packaging line. I am a strong proponent of one of President Reagan’s favorite phrases during nuclear disarmament talks: “Trust, but verify.” As I see it, there are several means to assure that the proper product is inserted into the proper package:

1. As the individual containers are opened to be loaded into the packaging lines, a hand-held NIRS or Raman unit may be used to affirm that the proper drug and dosage level is being loaded into the hopper. There need not be a sophisticated Chemometric algorithm involved, since hopefully QC has already analyzed the batch.
2. A second level of sophistication would involve an actual 100% verification of the tablets or capsules. A unit could either be built into or moved up to the active line and could scan the tablets, for example, as they are loaded from the bin(s) to the hopper. One supplier, exhibiting at IFPAC this year, is Indatech from Clapiers, France. They use a push-broom hyperspectral imaging spectrometer to scan and, if needed, analyze, each tablet, up to 800,000 per hour.
3. For more complex packaging, where more than one type of tablet or capsule is present in any package—i.e., clinical studies with two or more types per “card”—it is also possible to scan each blister prior to sealing.

While there is an argument that these devices can be expensive, I would refer the cynic to the story above about the multi-million-dollar lawsuit and ask which is less expensive. One is also mindful of the potential for human suffering in instances such as the unwanted pregnancy or potential overdoses, not merely the cost of recalls and resupplies.

In addition to the tablets or capsules, per se, the packaging materials may well be controlled by the same instrumentation. For example, there were several recalls (same company mentioned above)  for “strange odors” in products packaged in plastic bottles. The cause was the pallets upon which the bottles were stored; there was a preservative with a high vapor pressure whose vapors were able to permeate the plastic bottles. As mentioned earlier in  this article, you will see that we ascertained in 1971 that plastic permits gasses to pass. Surely someone could have remembered this fact and solved the problem after the first lot was recalled? Other applications, not so obvious are also performed by the instruments located in packaging. While the polymeric material for blisters should have been cleared in QC, there is seldom a good way to know that the side which is supposed to melt to the aluminum is facing the aluminum. If not, the heated rollers will get very messy. NIR or Raman will quickly ascertain which side is which.

If a “branded” company has trouble with occasional mislabeling, it will only be worse for a contract manufacturing organization (CMO), who will often package many more brands in a given time period. With smaller profit margins, a CMO can less afford a recall than the “mother-company.” It should be obvious that this “weak link” in the production chain should be fixed.

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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.