Getting drugs from the manufacturer to the end-user is a long, varied and circuitous process and it keeps getting longer — generating more risk and creating more opportunities for exposure to undesirable temperature conditions. Such exposure in the supply chain can produce deleterious results with regard to the quality of therapies, particularly among biological drug products. They are in fact, at a constant risk to damage as the result of deficiencies in the supply chain that are not always known, recognized or mitigated. Likewise, the effects they can produce are not always well understood and often only marginally characterized.

The rapid expansion of temperature-sensitive large molecule drug manufacturing combined with the surge in their global distribution has contributed greatly to the complexity of the supply chain and has warranted the need for greater knowledge and better control. At the same time, it has generated increased concern and scrutiny among regulatory authorities. Vipol Dholakia, from the FDA’s Center for Drug Evaluation & Research, stated that among the agency’s concerns for maintaining the quality of biological drug products are “increased risks from products requiring special storage needs, product sensitivity to temperature excursions, low temperature effects and more variety in distribution modes.”¹

We have seen unprecedented growth in these specialty drugs, and as the FDA has aptly pointed out, greater diversity in how they eventually get to the patient. This has broadened to include transport, from new lanes, models and modes, to innovative logistics and services, resulting in more gaps in the supply chain than many companies are capable of addressing. It’s a bit like playing the popular carnival midway game, Whack-A-Mole; just as you beat one back, another seems to pop up.  

The lengthening of the last mile presents some unique challenges for maintaining drug quality. I have long advocated the need for a simultaneous bottom-up push for improved handling of temperature-sensitive drugs and for regulatory compliance. But there is a chasm of not only distance but also expertise and interaction between those at the top of the supply chain and those at the bottom. In addition there is considerable misunderstanding and ignorance as to the importance of handing temperature-sensitive biological drugs. 

This has recently come to light at the doctor/patient level with the advent of a phenomenon dubbed by some rheumatologists as “Enbrel fading.” This unfortunate moniker, popping up among on-line discussion forums, support groups and blogs, refers to what has been repeatedly described as the loss of efficacy by patients taking Amgen’s rheumatoid arthritis miracle drug, Enbrel, over a period of several months. Complaints by patients to their doctors range from swings in levels of pain management dose-to-dose, inconsistent duration in effectiveness, and increases in inflammation as determined by nonspecific tests for monitoring treatment. Such setbacks have not only diminished the quality of life for these patients, they have caused increased anxiety and have added substantial costs to patient treatment with more visits to the doctor, the ordering of more diagnostic tests and more diversified drug treatments.
This fading condition is not unique to Enbrel, it turns out, as questions of inconsistencies in effectiveness have been highlighted for similar autoimmune-targeted, temperature-sensitive parenteral therapies.

Among the questions raised in search of an assignable cause for this fading effect are variabilities in process manufacturing and distribution. Where visibility in manufacturing is typically high and tightly controlled in a GMP process, distribution through the supply chain is not. Lapses in chain of temperature custody abound. Without the benefit of drug temperature provenance at the unit dose level (such as those carried on vaccines in developing countries), track-and-trace indicators, or other monitoring technology that can alert healthcare professionals, doctors and/or patients as to a drug’s quality at point-of-use, all we have to rely on is blind faith. We readily accept the convenience and rarely question the effectiveness of the medicines we buy off the shelf, or those that are prescribed by our doctor, administered at a clinic or hospital, purchased over the counter, or received through mail order pharmacy. We assume that they are pure, safe, and viable.

The growing risk and lack of visibility and control in the transportation and distribution chain, combined with what we still don’t fully understand about biological drugs, is cause for perpetuating a discourse on “Enbrel fading.” It may just be the consumer’s best hope for gaining mainstream media attention, drawing consumer awareness, forcing positive change and improving the quality of drug products.  

References

1. Dholakia, V., Center for Drug Evaluation & Research, USFDA, Presentation at HDMA Managing Cold Chain Products Conference, Baltimore, MD Aug. 2011

Kevin O’Donnell is a senior partner at Exelsius Cold Chain Management – U.S. He serves as chair for the International Air Transport Association (IATA) Time & Temperature Task Force, is a member of the USP Expert Committee on Packaging, Storage and Distribution, and is a temporary advisor to the WHO. He blogs at www.clutchcargo.us and can be reached at [email protected].