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"Smart" tags speak only when spoken to. "Brilliant" tags are capable of independent decision-making.
Drugs must be transported, stored, and ad-ministered in non-ideal environments. However, the stability labeling for many refrigerated drugs often allocates zero time for handing outside of the refrigerated norm of 2 to 8°C. Similarly, the labeling for "room temperature stable" drugs often allocates zero time for storage outside of about 2 to 25°C.
Stephen E. Zweig, Ph.D
In the real world, drugs are transported to where they may rest in uncontrolled storage or loading areas for some period of time. They may also be handled by healthcare workers who don't normally work in environments that meet these fictional "ideal" temperatures. To what extent is this disconnect between stability labeling and practical reality medically significant? Clearly this depends upon the drug in question. Many of the classical "small molecule" drugs are quite temperature stable, but other drugs, such as beta-lactam antibiotics and biotherapeutic proteins, are quite unstable. In this later example, undetected or undocumented temperature fluctuations can cause medically significant problems.
Here, recent experience cited from the vaccine field may prove relevant. Vaccines are biologic products and somewhat resemble therapeutic proteins in overall stability and other characteristics. Like therapeutic proteins and other temperature-sensitive drugs, vaccines can be rapidly destroyed by temperature extremes such as freezing or storage at elevated temperatures.1 Unlike therapeutic protein drugs, however, vaccine effectiveness is fairly easy to measure. After vaccination a blood sample can be drawn, and the presence or absence of antibodies against a particular vaccine antigen can be measured.
Vaccine researchers first realized that temperature control was a major concern as a result of large-scale, third-world immunization programs. Follow-up studies typically revealed that a large percentage of the population failed to respond to the vaccine. These vaccination failures drew attention to the high incidence of "cold-chain" breaks in the third world. Studies indicated that in the journey from the manufacturer to the ultimate end user, the vaccines passed through many hands (links in the chain), with numerous opportunities for the vaccines to be stored improperly. As a result of these studies, the World Health Organization (WHO) now requires that all WHO vaccines incorporate an easy-to-read time-temperature indicator (TTI)2 on the vaccine's label.3 This TTI lets users know at a glance if the vaccine is still viable.
Cold-chain breaks are not just a third-world problem. Surprisingly, a large number of follow-up vaccine storage studies have demonstrated that cold-chain breaks are also common in the United States and other first-world countries.4 Because vaccine deterioration (i.e., vaccination failure) is fairly easy to measure, vaccine workers are very sensitive to this issue. As a result, there are strict vaccine storage rules, including documenting the storage temperature on a twice-daily basis and strict standards for vaccine refrigerators.
But are vaccines and therapeutic drugs really all that different? Is the rate of cold-chain and stability failures for therapeutic drugs somehow substantially better than that of vaccines? This appears to be unlikely. The primary reason that cold-chain awareness is significantly lower in the pharmaceutical sector may be because drug failures caused by cold-chain breaks are harder to detect.
Over time, drugs can deteriorate into inactive, or even potentially harmful forms due to oxidation, hydrolysis, or any number of other side reactions. Each of these reactions advances in a temperature-dependent manner. At higher temperatures, these reactions usually speed up, and at lower temperatures they usually slow down. With certain exceptions, such as the denaturation of protein-based biotherapeutic drugs induced by freeze-thaw phase transitions, the actual rate of drug deterioration changes only slowly with temperature. Thus, a drug will generally deteriorate only slightly faster at 9°C than it will at 8°C.
Present drug labeling and stability testing almost universally ignores these basic chemical facts. At present, most temperature-sensitive drugs typically have labeling such as: "Store at 2°C to 8°C, do not freeze."
Envision some logical problems? What happens if the drug is stored at 9°C for one minute? Will the drug deteriorate into a less potent or even harmful form? What happens after one day at room temperature?
Present drug storage stability labeling has two types of problems. The first is that the labeling ignores well-known laws of chemical reactions such as the Arrhenius equation, and instead will typically take thermodynamically unrealistic positions (e.g., that 9°C is greatly different than 8° C). The second problem is that the labeling totally ignores human factors considerations. Clearly it is not possible for a health-care practitioner to take a drug from 2 to 8°C and instantly inject it into a patient. Rather, the drug will typically be removed from refrigeration, warmed to room temperature for some time, and then injected.
What if the drug is expensive and someone has left it out by mistake for an hour? Should it be thrown away or returned to the refrigerator? The attending healthcare worker usually makes decisions like this on an ad-hoc basis. But how can this be done on a rational or consistent basis? The nurse or physician isn't a stability expert, the detailed drug stability information is almost never published, and usually there is no precise record of how long the drug was left at an improper temperature.
One key aspect of the second human-factor problem is that the burden of making important drug stability decisions has been passed from organizations with a high knowledge of the drug's stability (e.g., the manufacturer) to healthcare workers with less knowledge of drug stability. The consequence of violating the labeling, which happens constantly because of unrealistic labeling, is guesswork concerning a drug's viability. Will the drug be only slightly less potent? Will the drug deteriorate into a harmful form? Is there a safety margin? Are busy health-care workers who have little information really the best people to make this decision?
In this instance, the third-world is actually somewhat more advanced than the first-world. Tropical medicine experts are well aware that present drug labeling is inadequate when drugs are stored under tropical conditions. As a result, they conduct their own independent stability testing and publish supplemental storage guidelines for tropical conditions.
The WHO mandate that all vaccines must incorporate chemical time-temperature labels that let users know if the vaccine has been damaged by heat suggests an interesting possibility. What if it was possible to put a stability-indicating time-temperature label on all drugs with marginal stability?
Unfortunately present chemical time-temperature indicators (cTTI) are not precise enough for these applications. cTTIs usually require users to do some sort of color matching comparison, which can be interpreted differently by different people. cTTIs have the additional problem that they cannot accommodate complex degradation kinetics such as when damage occurs at both low and high temperatures. In spite of these drawbacks, cTTIs are a step in the right direction.
In addition to cTTIs, many different time-temperature loggers are commercially available.5 Although highly accurate and capable of storing large amounts of temperature data, such loggers are not easy to use. The logger data must be downloaded, transmitted to a remote site where the data can be analyzed, and the results then transmitted to the user. Although well suited for monitoring shipments of bulk quantities of drugs, this is a cumbersome process not well suited for most everyday health-care applications.
The basic cTTI concept of an "instant stability assessment" is nearly ideal, but the flexibility and accuracy of this approach needs to be upgraded to meet the high accuracy demanded by therapeutic proteins and other modern drugs. Is there a way to utilize modern electronics to perfect this concept? Are more precise electronic time-temperature indicators (eTTI) feasible?
Most readers of this article are probably well aware of the initiative to incorporate RFID tags into standard drug packaging (Figure 1).6 This initiative is designed to detect counterfeit drugs and protect product integrity. RFID tags, which typically cost less than a dollar, clearly demonstrate that modern electronics are capable of putting an impressive amount of computing power and radio-frequency capability into a paper-thin and inexpensive label. RFID tags usually avoid the cost and complexity of needing an onboard battery by using a "passive" design that draws power from the energy provided by the RFID tag reader. Thus these tags are not powered when the tag is not being read. Although they are called "smart" tags, they speak only when spoken to. They are smart, but not quite smart enough.
Figure 1. RFID Tags Monitor Time and Temperature
Instead of a "smart" tag that speaks only when spoken to, drug stability monitoring requires a "brilliant" tag capable of independent decision-making. A brilliant tag must be continually thinking and calculating, even when the tag is not being read. Ideally the brilliant tag will either visually display the drug status (good, not good) on a continual basis, or immediately transmit the drug status to the user when an RFID reader reads the tag.
Figure 2. Electronic Stability Monitoring
Clearly for this to work, a brilliant tag must use an ultra-low-power microprocessor that is always turned on. This microprocessor must continually sample the ambient temperature and perform stability calculations using a sophisticated drug stability model. Figures 1– 3 illustrate how such a sophisticated drug stability model can work.
Drugs typically remain viable for several years. For this brilliant tag to be practical, it must have a tiny paper-thin battery, an economical price, and an ultra-low-power microprocessor that can run for several years off small amounts of power available from a tiny battery. Is modern electronics up to this task?
Fortunately it is. Low-cost, paper-thin batteries are commercially available. Paper-thin batteries produced by ultra-low-cost printing processes are available with dimensions such as a 39 mm x 39 mm x 0.7 mm (1.5 inches x 1.5 inches x .03 inches) thick battery (0.06 inches thick for a two-cell battery capable of delivering 3V). These batteries feature lifetimes of three years and a power capacity of 30 milliamp hours (mAh). More conventional coin-sized batteries are available for a cost of only a few cents each. Coin-sized batteries can deliver 220 mAh of current at 3V and last for up to ten years.
Figure 3. Stability Algorithm for Insulin
Suitable high-performance, economical, and ultra-low-power microprocessors also are available. For example, 16-bit microprocessors are available that run on as little as 0.8 microamps current and cost less than 50 cents.7 This 16-bit microprocessor has a computing capability that compares favorably with that of the original IBM personal computer, and would run for up to 3.4 years with paper-thin batteries, or more than 10 years from coin cell batteries. Less sophisticated, but still adequate 8-bit and 4-bit microprocessors are also available and cost less than 25 cents a piece.
A suitable microprocessor can be linked to an RFID chip to construct a battery-assisted RFID tag. This type of tag is a cross between a passive RFID tag not powered when not operational, and an active RFID tag that uses battery power to send and receive radio signals. A battery-assisted RFID tag remains continually powered, but saves battery energy by utilizing the reader's energy source to transmit back an RFID signal.
Thus, in volume, modern electronics is presently capable of producing drug stability monitoring "brilliant" tags for around $1.00 to $2.00 per unit.
Although the technology is available today, there are a number of significant manufacturing, regulatory, and legal issues that must be addressed before this "brilliant tag" approach can become widely used for drug stability monitoring.
To program a "brilliant tag" accurately, stability characteristics of the drug must be precisely determined. This will likely require drug manufacturers to pay increased attention to their drug stability testing procedures. Fortunately drug companies typically conduct much more stability testing than is usually published, and much of this needed extra information is likely to be available. Here "brilliant tags" act to liberate this detailed information, which otherwise would go unused, and make it available to the end user in a convenient, timely, and easy-to-use format. The net effect is brilliant tags enable the company to send its stability experts to monitor the status of each unit of drug in the field.
An additional advantage from a manufacturing perspective is that brilliant tags enable a pharmaceutical company to have more strategic options during product development. Consider a promising drug in late-stage development that has marginal stability. Without brilliant tags, a manufacturer would have to decide between two undesirable options: terminate the drug or launch the drug with suboptimal storage dating. With brilliant tags, a third option is created: design an appropriate stability label that will flag any drug that has been improperly stored.
Brilliant tags are new, and regulatory policies concerning these tags have yet to be formulated. One possible regulatory policy may be to permit brilliant tag use on the stipulation that all existing storage regulations remain, and that the tags should never extend beyond a printed expiration date. In this instance, the tag would always indicate an expiration date less than or equal to the printed expiration labeling and serve as a secondary fail-safe device rather than as a primary process control device.
Legal considerations also are important. Brilliant tags transfer some of the burden of deciding when a drug is acceptable from the end user to the manufacturer. Although this is sound policy from both a safety and information-ownership perspective, it places a higher burden of the responsibility on the manufacturer. Mitigating this higher burden is the fact that a fair number of presently inexplicable adverse drug reactions may now become explainable and attributable to end-user failure to respond to appropriate stability warnings. This would tend to considerably reduce the manufacturer's legal burden.
One interesting issue is the concept of "standard of practice." After it becomes clear that a new "standard of practice" is available to minimize problems, legal considerations tend to favor manufacturers that adhere to the new standards.
Most drugs deteriorate gradually as they age beyond their expiration conditions. Fortunately, a slight loss in potency usually has only a small effect relative to overall physiological variation. As a result most drug deterioration is harmless and goes completely undetected.
There are exceptions, however. Drugs stored in a liquid form generally deteriorate much more rapidly than drugs stored in a dry form; and poor storage of liquid drugs can significantly compromise effectiveness. Some commonly used drugs such as beta-lactam antibiotics are particularly unstable, deteriorating after only a few hours of higher temperature exposure.
Drugs stored in non-temperature controlled environments such as ambulances also have many stability issues. Ambulatory infusion situations are particularly problematic because the drug is both in an unstable liquid form and subjected to uncontrolled temperatures.
Therapeutic proteins, in particular recombinant analogs of naturally occurring hormones and other body proteins, are another area where improved stability monitoring could prove useful. Degraded proteins tend to aggregate and also can assume other unnatural chemical states. These unnatural states tend to activate the body's immune system, potentially creating an immune response against the therapeutic protein. Such antibodies can act to neutralize the effect of the therapeutic protein, or worse, act to neutralize the effect of the body's own naturally occurring hormones. In these cases the degraded form of the drug can prove to be potentially harmful.8 Fortunately such recombinant protein therapeutics tend to be high-value drugs and can easily support the relatively minor additional costs of brilliant-tag packaging.
Brilliant tag technology can help insure availability of safe drugs in emergency situations, help promote ambulatory infusion, and potentially help minimize adverse drug reactions to certain classes of therapeutic proteins.
Due to advances in modern electronics, inadvertent use of temperature-deteriorated drugs is now a preventable problem. Brilliant tags are now available for pilot evaluation studies. These tags can be rapidly programmed to simulate the temperature stability of almost any drug. As this type of brilliant tag becomes more widely used, volume manufacturing should drive the cost-per-tag down to where they may become a viable option for nearly all temperature-sensitive drugs and vaccines.
Stephen E. Zweig, Ph.D., CEO, CliniSense Corporation, 15466 Los Gatos Blvd., 109-355, Los Gatos, CA 95032, 408.348.1495, email@example.com
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2. Heatmarker, TempTime Corporation, Morris Plains, New Jersey http://www.lifelinestechnology.com/health.html.
3. World Health Organization. Technical review of vaccine vial monitor implementation. http://www.who.int/vaccines-access/vacman/vvm/vvmforall.htm, 2002.
4. Bell, et. al. Risk Factors for Improper Vaccine Storage and Handling in Private Provider Offices. Pediatrics 2001; 107(6); E100.
5 Zweig SE. Technologies for monitoring IVD stability. IVD Technology 10(5) 59-63, June 2004.
6. Food and Drug Administration Combating counterfeit drugs: A report of the Food and Drug Administration. 2004. http://www.fda.gov/oc/initiatives/counterfeit/report02_04.html.
7. Texas Instruments, MSP430 microprocessor, http://www.msp430.com.
8. Rosenberg A, Worobec A. A Risk-Based Approach to Immunogenicity Concerns of Therapeutic Protein Products, Part 2: Considering Host-Specific and Product-Specific Factors Impacting Immunogenicity. Biopharm International, December 1, 2004.