RFID, or radio frequency identification, has tremendous potential value in monitoring biologics, as they are often high-value products and require strict temperature monitoring during production and shipping. But there have been lingering concerns, at least within FDA, that RF waves could have a measurable thermal or magnetic impact upon biologic drugs. The Agency’s 2004 guidelines regarding the use of RFID exclude biologics applications until enough testing has been done to negate these fears.
Two research faculty from the University of South Florida Polytechnic, Ismail Uysal and Jean-Pierre Emond, are working to put such fears to rest. With support from Abbott Labs, they’ve recently conducted studies of some 100 biologic drugs from eight different manufacturers, and have concluded that various ranges of RF frequencies used in common biopharma applications—from high-frequency (13.56 MHz) to ultra high-frequency (even up to 2.4 GHz)—have no significant impact upon the product.
The following is our email correspondence with Uysal and Emond:
PhM: First, what prompted your studies? How does your work build upon or break new ground from previous research?
Uysal and Emond: Regarding use of RFID technologies in the pharmaceutical industry, FDA has published a detailed document in the form of a compliance policy guide, called CPG Sec 400.210, where they outline multiple parameters which would apply to any pilot study using RFID. However, drugs approved under a Biologics License Application (BLA) or protein drugs covered by a New Drug Application (NDA) are excluded from any such study mostly because of concerns about the effects of RF radiation (thermal or non-thermal) on biologics. The thermal effects have been studied extensively in the literature, a good example would be by H. Bassen of FDA on his paper titled, “Liquid pharmaceuticals and 915MHz RFID systems, worst case heating and induced electric fields,” where they used output power levels of 200-350W that are much higher than the currently FCC regulated level of 4W. They found out that in the worst-case scenario the temperature rise was limited to 1.7°C which was considered insignificant to create any undesirable effect. Another example is the Accenture Jumpstart study where they looked at the impact of RF exposure but more specifically on product temperature.
However, there aren’t many studies which also looked at the non-thermal effects which can be observed in the structure of the protein. Clive Hohberger looked at both thermal and non-thermal effects of RF on blood products (a category of biologics) but only at HF frequency of 13.56MHz. Based on this observation we set out to investigate the effects of RF on a much wider frequency range (13.56MHz to 2.4GHz) and on a greater variety of biopharmaceutical products (vaccines, hormones, immunoglobulins) from many different companies. This way, we could have a much comprehensive study which has never been done in the past.
PhM: In the past, some biologics manufacturers have been reluctant to provide product for such studies (perhaps out of fear of what might be revealed about impact to their products). How did you get buy-in from the 8 companies whose products were used? Was Abbott’s support the catalyst?
Uysal and Emond: It all started during the 2009 UF Academic Cold Chain Pharmaceutical Conference, where our team brought to the attention to the pharmaceutical industry the potential of using RFID in the cold chain. Dave Ulrich and Scott Rasmussen from Abbott decided to take the lead and bring funding and technical support to start the study. The RFID laboratory at University of Florida provided personnel, laboratories, and scientific equipment to undertake this one-year project. The PDA PCCIG (Pharmaceutical Cold Chain Interest Group) reached to other companies and in a very short time eight companies volunteered to participate in this study.
PhM: One of your goals is to have biologics removed from a list of "exceptions" regarding the use of RFID technology around pharmaceutical products. Is this likely? In your opinion, what is FDA’s current stance on this topic and why is it hesitant to remove biologics from the list?
Uysal and Emond: We haven’t discussed this issue with FDA enough to have a say in this question. After the first set of results started coming in showing there was no effect on the protein structure due to RF exposure, we presented our work in several conferences and participated in Q&A session with a few members of the FDA after our presentations and Abbott had some conversations with FDA so our study definitely had some exposure (no pun intended!) but at this point in time it is really difficult to say whether FDA will remove the limitation or if they are hesitant to do so for other concerns. But science shows both the thermal and non-thermal effects of RF are insignificant and we hope they will take note of this.
PhM: Your conclusions say that the products were not “adversely affected” by exposure to common RF signals at standard frequencies. However, were there minor impacts or changes to any of the products?
Uysal and Emond: The test methods that each pharmaceutical company applied to measure the adverse effects of RF radiation on the products were different and proprietary so they didn’t share the details with us. The type of correspondence we had with the companies in regards to the results of their protein purity study was digital, 1 or 0, i.e., the exposed products were either the same as the non-exposed (control) products or adversely affected. There was no quantification in terms of the effects being major or minor.
PhM: I understand that you were assessing “non-thermal RF transmission,” or whether the radiation itself impacted product. Why is this a significant distinction? Did you look at the thermal impact upon the product as well? Were there instances in which product temperature was elevated?
Uysal and Emond: The distinction comes from the fact that the products were inside a sealed anechoic chamber which was temperature controlled. In other words, RF transmission could not heat the products (except extremely localized effects) beyond their specific temperature range since the temperature of the room is always held at a nearly constant 4-6°C which effects the product temperature. Thus, any effect we see in the protein structure is “non-thermal”, in other words it’s not due to the heating effect but rather due to magnetic (for HF) or electromagnetic (for UHF) radiation resonating and damaging the protein structure. As I mentioned above in the literature there are different studies looking at thermal effects but we wanted to concentrate on the non-thermal side.
We looked briefly at how the product temperature changed during our experiments by placing thermal couples in some of the vials/cases. An informal analysis of our results showed that the temperature increase due to RF was less than 0.2-0.3°C, but like I said this wasn’t the part we were most interested in.
PhM: Finally, what surprised you? What did you learn that you didn’t anticipate?
Uysal and Emond: Based on science, and the size of a typical RF wave (about 10cm for 2.4GHz, about 30cm for 915MHz) being much larger than the size of a protein (50Å which is 10 to the power (-10) meters, so it’s really small) our hypothesis was that there shouldn’t be any non-thermal effect. So in this case, we weren’t really surprised by the results. We weren’t anticipating such a high level of effort required by our research team to first design the test protocol and then develop the hardware around it, it wasn’t easy but we learned a lot in the process and now have a state-of-the-art test facility with the latest hardware and a temperature controlled anechoic chamber that can be used in further studies like this, so we’re definitely glad to be an initiator and participant of this study.