Recent events surrounding the contamination of heparin supplied by a Chinese API manufacturer bring home the risks and realities of our expanding global economy. it’s clear that the complexities of maintaining the integrity of the products we manufacture are escalating. In his landmark book, “The World is Flat,” Thomas Friedman describes 10 “flatteners” which are leveling the playing field in the world marketplace. Number five on the list is the global supply chain.
The option of low-cost supply and manufacturing alternatives in emerging countries has become a lure our industry has found impossible to resist. In an era marked by unprecedented consolidation and shareholder, patient and government pressure to become more efficient, effective and cost-sensitive in producing new therapies, the promise of low-cost partnering appears to be the answer to our prayers. However, this new opportunity brings new risk. How do we ensure that the products we deliver to our customers meet our own high quality standards?
The World Health Organization (WHO) speculates that one in four packets of drugs dispensed in Southeast Asia is counterfeit. A study published in the PLoS Medicine journal in 2006 stated that the percentage of anti-malaria drugs containing no active ingredients at all had increased from 38% to 53% in Southeast Asian and African markets. While counterfeiting and adulteration may have different root causes, they have the same impact on the public and represent an imminent danger to our standing in the marketplace and to the public’s confidence in our ability to deliver safe therapies.
FDA has recognized this. in 2004, it issued its first guidance to industry concerning the integrity of the global supply chain. The concept was to trace and verify a product as it moved around the globe, thereby establishing the “pedigree” of the ingredients and products manufactured, marking a trail between supplier, manufacturer and distributor. The enforcement of this guidance was delayed because industry felt it was not in a position to leverage the Agency’s recommendations, and so did little to nothing.
As a result, FDA issued its drug pedigree final guidance in 2006. As with Process Analytical Technology (PAT), we as an industry started to look to new methods and ways of applying technology to ensure product pedigree. Radio frequency identification (RFID) quickly became the technology of interest. But, just as with PAT, we have been slow to move forward. What is holding us back? In a word, costs. I believe that assuring a global supply chain must not only satisfy the needs of the public but also the needs of business. Technology solutions, while robust, can be defeated if they are not implemented properly.
RFID at the unit level is costly, and only high-margin therapies become practical candidates. With the percentage of generic drugs entering the marketplace exceeding 50% and escalating on a yearly basis, this solution by itself would not meet the needs of business or the marketplace. So what is the answer? We should look at the entire global supply chain as a system that must be designed to guarantee process stability and predictability. The irony of this view is that we find ourselves in the midst of the largest transformation the industry has seen in the last fifty years.
We embrace principles such as Six Sigma, lean manufacturing, risk management and Quality by Design (QbD) in the hopes of leveraging leading-edge opportunities such as pAt, and we find ourselves reexamining and reinventing how we ensure product quality and process stability. PAT cannot succeed without sound process understanding. Similarly, RFID cannot succeed in ensuring the integrity of the drug pedigree without a sound understanding of the key parameters which drive its performance and variation.
So what does the roadmap look like if we are to achieve the objectives of the drug pedigree guidance? As with all optimization initiatives, I believe it starts with setting out a clear charter and metrics for success. The basis for the success metrics are found within the strategic goals of an organization.
Whether business objectives are tied to improved financial performance or market expansion, tying the success of the e-pedigree process to corporate performance will help frame your final implementation strategy. While RFID solutions have been cost-prohibitive in the past, today there are RFID labeling solutions that cost a fraction of a cent per unit container to implement, through the economies of scale offered by volume.
Combine this with RFID labeling applied to tertiary packaging, containerized shippers that can track and identify an unplanned intervention, as well as integration of RFID technology with existing supply tracking technologies (i.e., 2-D barcoding) as a hybrid solution, and visibility into the details of your supply chain becomes easy.
The next step in securing the supply chain is determining where the potential threats to the process exist and ascertaining what level of countermeasure is appropriate. While we would ideally like to design our supply chains with the strictest, most advanced countermeasures, this is not always practical. So the basic tenet of drug pedigree is focused risk management.
You can use the framework defined in ICH Q9 as a model. This risk assessment, sometimes called a threat model, needs to be applied to the entire supply chain for all components of interest. Evaluating this risk as part of a threat model allows us to quantify and compartmentalize risk across the supply chain.
It also promotes the evaluation of every facet of the global supply chain, including transportation, distribution, electronic (IT), personnel and process uncertainty (unanticipated contamination) as part of a holistic assessment process. This exercise will reveal that threats exist inside and outside the organization.
For example, recently the FBI reported that a large number of counterfeit routers were showing up in Asian markets and had made their way into military and FBI networks. The investigation revealed that some Cisco contract manufacturers were making the counterfeit units in their own Asian facilities after hours. Either there were no countermeasures in place to prevent an internal counterfeit risk or the internal auditors were complicit with the counterfeiters.
The Achilles heel of most RFID systems is data management. Making sure that lot identifier data cannot be downloaded to a USB portable drive or emailed to an unapproved recipient are just two simple precautions that must be addressed in high-risk environments. Once the threat model has identified and categorized a countermeasure plan, implementation is next.
Implementing an e-pedigree solution can be technically complex or elegantly simple. The challenge is managing organization change along with the appropriate training, policies and procedures. Treating the implementation of an e-pedigree solution as you would any new unit operation in your process is the key to effective implementation. Developing robust process streams through the use of structured analysis or value stream mapping will help eliminate unplanned variations in your pedigree process stream.
Applying the same principles used for GMP database management can ensure that the foundation of your pedigree solution is in control and secure. If we as an industry wish to leverage low-cost suppliers and manufacturers in emerging markets, and are willing to invest in solutions for everything from IP protection to product branding, we must make certain we can supply safe, efficacious therapies to the marketplace.
Our industry has risen to the challenge before. To restore customer confidence when Tylenol was adulterated in 1982, we responded with myriad tamper-evident systems that have become standard, and our communication program ensured that our customers understood the benefit of our actions quickly. The experience we acquire as we adopt programs such as Operational Excellence, QbD and ICH Q9 provide the tools and approaches necessary to effectively ensure our global supply chain today. Our desire to do this can no longer be optional if we are to succeed and thrive in the years to come.
