Controlling Variability and Vulnerability in the Pharmaceutical Supply Chain

Threats to the supply chain aren't going away and the underlying regulatory environment, both in the United States and in other regions, does not appear to be converging on any one formula.

Supply chain challenges are abound, regardless of the industry. Macroeconomic trends haven't helped: globalization requires longer and more complicated supply lines, inventory systems and distribution networks; outsourcing has introduced a greater number of entities into the supply chain; and economic pressures have forced manufacturers to reduce time-to-market.

At a granular level, these trends introduce more variability into a product's journey through the complex web of suppliers, manufacturers and distributors. Manufacturers rely on a secure supply chain for the movement of materials, parts and finished goods. One of the most difficult activities is maintaining visibility as each part moves through the supply chain. Achieving this visibility is critical, as any crack in the supply "chain" can have disastrous results.

The Drug Supply Chain: Global and Under Attack

In the past two years, three incidents have greatly affected the U.S. drug supply chain. The Heparin incident in 2008 resulted in 81 deaths and put thousands of other lives at risk. The popular blood thinner was recalled because a tainted ingredient was used by a contract manufacturer located in a developing region that had lower standards for raw materials.

As economic pressures mount, we will continue to see a rise in outsourcing and contract manufacturing. Why? Pharmaceutical manufacturers are faced with pressures to keep costs low and bring products to market faster. The difficulty is that outsourcing presents a new set of problems that challenge supply chain integrity and complicate supply chain visibility.

The second incident occurred in 2009 when there was a massive drop in the potency of the H1N1 vaccine. Sanofi-Aventis was forced to recall approximately 800,000 doses of its U.S.-distributed H1N1 vaccine for children after tests showed that certain batches had lost potency over time. AstraZeneca found itself in a similar situation after nine lots of its attenuated intranasal H1N1 vaccine failed stability tests. As a result the company had to voluntarily recall 4.7 million doses. In both instances improper storage was found to be the root cause.

The U.S. Centers for Disease Control and Prevention notes the importance of proper cold chain storage and shipment to vaccine potency. It estimates that 17% to 37% of providers expose vaccines to improper storage temperatures.
Another, more recent, recall occurred in January, when Johnson & Johnson announced a voluntary recall of several hundred batches of popular medicines, including Benadryl, Motrin, Rolaids, Simply Sleep, St. Joseph Aspirin and Tylenol. The recall was initiated over complaints of a musty smell, which experts suspect was the result of the packaging being contaminated with the chemical 2,4,6-tribromoanisole. According to the United States Food and Drug Administration (FDA), this recall came 20 months after McNeil first began investigating consumer complaints about moldy-smelling bottles of Tylenol Arthritis Relief caplets. The recall included 53 million bottles of over-the-counter products.

On April 30, 2010, another recall was issued for 40 products including liquid infant and children's pain relievers, Tylenol and Motrin, and allergy medications Zyrtec and Benadryl. An FDA report said its inspectors found thick dust and grime covering certain equipment, a hole in the ceiling and duct tape-covered pipes at the Fort Washington, Pennsylvania, facility, which made all of the 40 recalled products.

Just last month, the FDA confirmed that the bacteria found at the Johnson & Johnson plant was Burkholderia cepacia. The CDC has since stated that Burkholderia cepacia would not likely cause health problems for those with healthy immune systems, but those with compromised immune systems could be more susceptible to infection.

With health consequences ranging from infection to life-threatening reactions, security measures at every point in the supply chain are even more integral to ensuring patient safety. Storage isn't the first variable that comes to mind when a drug is recalled, nor is moldy manufacturing equipment, but these incidents certainly highlight a few of the factors that can affect a finished product.

Controlling Variability

Proven solutions are available that are capable of safeguarding the drug supply chain. These include electronic pedigrees (e-Pedigrees) and RFID, which provide a documented and complete history of a given product's chain of custody, from the manufacturer to the point of dispensing. The problem is that governments have been slow to take action with technologies such as e-Pedigree and as a result are increasing the likelihood that counterfeit items can enter the drug supply chain.

Another method of ascertaining the integrity of a product is spectroscopy. Spectroscopy uses the light-scattering properties of molecules to generate a unique spectrum, or chemical fingerprint, of most products. The benefit of this technique is that raw materials and finished products can be thoroughly, non-invasively analyzed.

Following are further details on these techniques, including the pros and cons of each solution:

RFID/ePedigree

E-Pedigrees and RFID tagging (or another track and trace method) provide a comprehensive set of tools to bear on securing the legitimate supply chain. Product information such as national drug codes, lot numbers and expiration dates are gathered from the original manufacturing process. These codes are then securely linked to extensive transaction detail covering the changes of possession that a drug undergoes from manufacture to final distribution to patients. If serialized products are shipped, these numbers are also incorporated into the pedigree. As a result, the e-Pedigree secures the chain of custody, which ultimately prevents phony transactions and products from getting into or remaining in the legitimate supply chain.

The downside -- and this is common to any technology -- is that RFID is extremely costly from an operational standpoint. Specifically, it requires additional manpower and introduces some technology hurdles that must be overcome before it can be more broadly applied. For example, each individual pallet or package requires an individual RFID chip which, despite a decreasing price tag, still generally costs between 7-15 cents each. There are also unsettled questions about whether the RF energy used to read the tags may impact sensitive biologics. Lastly, like any packaging technology, a major limitation is that it does not secure the product itself, making it largely irrelevant in markets where the product is sold without its original packaging. This is where spectroscopy comes into play.

Spectroscopy

Spectroscopy can be used to accurately identify the chemical make-up of raw materials and finished products at ports of inspection, loading docks, points of sale and manufacturing plants. The benefit of this technique is that raw materials and finished products are analyzed at the chemical level, which delivers accurate results.

Increasing Quality Control at the Beginning of the Supply Chain: Lonza Case Study

Lonza Biologics' facility in Portsmouth, New Hampshire, was looking to tighten its raw material quality control processes -- particularly the sampling required in material identification testing. The contract manufacturer conducted a study of portable spectroscopic technologies -- Raman, near-infrared (NIR), and Fourier Transform infrared (FTIR) in order to speed its raw material analysis while maintaining accuracy.

Lonza found that in terms of achieving its goals, Raman and NIR outperformed FTIR because the two technologies eliminate the need for sampling raw materials for identification testing. The Raman and NIR solutions could scan through packaging, which FTIR was not capable of.

Another parameter when evaluating these technologies was the ability to create reference scans. Though all three technologies had this ability, Raman and FTIR only required one lot of material to create the reference scan. FTIR required direct contact with the material, which Lonza wanted to avoid since the ultimate goal was to limit contact with the material. The Raman reference scan was created using a single lot of material.

The study wasn't able to test NIRs capability because it takes more than one lot of material to obtain a robust library. As a result, Raman and FTIR were scored the highest.

The final criterion in the study was to eliminate contact with the material as much as possible. The evaluation showed that Raman stood out from the other technologies for its ability to accurately identify substances through multiple sample containers.

Given these results, Lonza is using five handheld Raman units at its biopharma sites and has seen immediate ROI by harmonizing specs on ten raw materials.
Currently there are several technologies that use spectrometry, including Fourier Transform infrared (FTIR), near infrared (NIR) and Raman spectroscopy. For the purposes of this discussion we will focus on the latter two. NIR is a well-known spectroscopic technique that measures molecular vibrations and can be used to identify the individual chemical components of a drug or raw material. NIR is less selective than other forms of vibrational spectroscopy, and therefore requires a greater investment of manpower in order to create and maintain robust material libraries. However, once properly installed, NIR systems can provide very quick, reliable results.

Raman spectroscopy is less well-known than NIR, but has been a game-changer in the industry since becoming available as a portable, handheld instrument. This technology can be used in the supply chain to accurately identify chemicals without having to come into direct contact with the substance (i.e. it can scan through sealed glass, plastic bottles, bags and blister packs). This is made possible through its user of a laser which illuminates a sample and measures the molecular shift that occurs. Handheld Raman spectroscopy is currently being used by a majority of the largest pharmaceutical manufacturers, as well as regulatory bodies around the world.

FTIR has the same specificity as Raman and can be used with certain materials that are challenging with Raman. However, it does not allow for non-contact sampling like Raman and NIR and therefore is less convenient for broad supply chain screening applications.

Conclusion

The recent incidents cited earlier in this article make one thing clear: threats to pharmaceutical supply chain aren't going away and the underlying regulatory environment, both in the United States and in other regions, does not appear to be converging on any one formula. The ideal solutions are those capable of tracking and authenticating product from the earliest point in the supply chain all the way until it reaches the consumer. For many, the winning formula will incorporate some combination of the technologies reviewed in this article, which in the end will allow these businesses to ensure the quality and safety of the drugs that consumers count on each and every day.

Duane Sword is Vice President of Thermo Fisher Scientific.


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