Peter Seidl, Schreiner MediPharm

Fig. 1. Peel-off labels allow healthcare providers to better document drug administration.

		Among the many challenges the pharmaceutical industry is facing today, patient safety remains key. Within a complex regulatory landscape, as well as diversified markets and medications, it is even more important to ensure safe drug administration for healthcare providers and consumers alike. Sophisticated label solutions can play an important role in supporting product and patient safety.

		Initially, the label serves to clearly and reliably mark the pharmaceutical product by providing information on the product, its administration, batch number, expiry date, etc. However, dosage forms and drug delivery methods can vary widely, so the label design has to be optimally tailored to meet the specific requirements of the medication. Ideally, the label provides additional functionalities that add value to the product by enhancing user friendliness and product safety.

Helping avoid medication errors: labels with detachable parts

		According to the World Alliance for Patient Safety 2010, annual medication errors cost between $5.8 billion and $27.3 billion worldwide. In the United States alone, an estimated 7,000 people die every year due to inappropriately dispensed drugs. A report published by the Institute of Medicine (IOM) in July 2006 concludes that labeling and packaging issues are the cause of 33% of all medication errors and 30% of fatalities from medication errors.* The report also pointed out that “product naming, labeling and packaging should be designed for the end user—the provider in the clinical environment and/or the consumer.”

* Aspden P, Wolcott JA, Bootman JL, Cronenwett LR, eds. Preventing Medication Errors. Institute of Medicine, The National Academies Press: Washington DC. 2006.

		In September 2007, the Prescription Drug User Fee Act (PDUFA IV) was signed into law as part of the Food and Drug Administration Amendments Act (FDAAA). In this context, FDA committed to certain goals to reduce medication errors related to, among other issues, error-prone labeling and packaging designs. In June 2010, FDA held a public workshop to receive comments on the topic of medication error reduction. This resulted in a Draft Guidance “Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors,” published in April 2013.

		One of the recommendations included in the FDA’s draft guidance refers to “transferrable or peel-off labels for injectable medications,” emphasizing the fact that refilling injection solutions from, e.g., a vial or ampoule into an unlabeled disposable syringe harbors a particularly high risk of medication errors, since this might lead to administration of the wrong drug or wrong strength. By equipping the primary container with a label, including an integrated peel-off part, such instances could be avoided. The peel-off part is instantly available at the point of product preparation and can be easily and reliably attached to the unmarked syringe. Besides, it cannot be accidentally discarded as in the case of auxiliary labels provided with the carton.

		A cost-effective, yet intelligent solution to meet the above recommendations could be a single layered peel-off label, which due to its special design, is particularly suited for labeling small containers for single-dose applications, such as ampoules and vials. The label can be easily wrapped around the container and provides sufficient space for all critical information, as well as for the inscription of variable data and printing of barcodes. The detachable part contains the product name, the barcode, an area for post-printing of variable data, as well as space for manual inscription of dose, date and administrator’s signature. Thus, it is ensured that all crucial information is directly available at the disposable syringe after reconstitution. The detachable part can be applied to the syringe like a flag without covering the graduation lines. The product information is easy to read and scanning of the code is simple. For greater ease of use when wearing gloves, the detachable part slightly lifts, so it can be easily peeled off when the label is opened.

		More sophisticated solutions of peel-off labels feature multiple layers to accommodate several detachable parts and are mainly suited for multi-dose containers. They can be adapted to all kinds of primary containers and specific customer applications and demand extensive know-how in material and advanced printing technologies.

		Efficient and safe drug administration plays an important role in daily healthcare practice. Intelligent, multi-functional label solutions can help optimize processes in healthcare environments and thus contribute to patient safety. Only to mention one example: A hanger label for infusion bottles, which provides extended space for text information and additional detachable parts.

		Due to the multi-layered design, the label offers enough space for detailed product descriptions; while the integrated hanger allows the administering caregiver to quickly and easily hang the infusion bottle on a bedside rack. With the help of additionally integrated detachable label parts, the infusion can be documented in the patient’s medical records as well as the hospital files, thus ensuring reliable documentation and traceability of the medication. An alternative, even more sophisticated approach would be the addition of a paper booklet with many pages for texts in different languages.

Fig. 2. The Needle-Trap combines labeling with stick prevention

		A growing number of injectables are administered in prefilled syringes, which are ready to use and easy to handle. However, needlestick injuries harbor a high risk for healthcare personnel to be infected by contaminated blood after the injection. Roughly 3.5 million work-related needlestick injuries occur globally every year. Regulatory requirements by the US FDA and NIOSH demand that sharps instruments have to be equipped with safety devices. Also, in the European Union, member states had to implement directive 2010/32/EU on the prevention of sharps injuries into national legislation in May 2013.

		By integrating the safety mechanism into the syringe label, regulatory demands can be met in a smart and user-friendly manner. The compact design of the needle trap label allows the blood-contaminated needle to be simply and safely secured after the injection, and can be easily operated by healthcare personnel in a controlled, single-handed fashion. After the needle is locked into the plastic trap, it is irreversibly protected.

		Additional features to cover patient safety aspects may be integrated into the label, like peel-off parts for documentation of the administered injection, graduation lines for delivery of the right dose or anti-counterfeiting features for product security and brand protection.

		Packaging and labeling are critical to product authentication and should provide a reliable hurdle against counterfeiting and tampering. Due to international regulations, serialization and tracking of a product through the complete supply chain becomes a growing issue. Following the recently signed Drug Quality and Security Act (DQSA), FDA has started work on a US-wide track and trace system. Also, in Europe, directive 2011/62/EU will have an impact on packaging and labeling. The ultimate goal is to find solutions to clearly authenticate and secure drugs through the supply chain. Labels including, for instance, 2D matrix codes or alphanumeric codes for online authentication ensure traceability and authentication on the unit level.

		In general, integrated security concepts should ideally combine several security technologies in a multi-layered approach including overt and covert features. Thus, a customized solution could for instance include overt technologies like holograms, color-shifting inks, guilloche, micro-text printing or thermochromic inks. Covert technologies, like voiding effects, special pigments that can only be seen by a special reader, or luminescent digital watermarks, etc., would only be visible for informed experts. Ultimately, the objective should be to work closely with the pharmaceutical manufacturer in a consultative approach in order to find the ideal solution that suits his specific security requirements, while integrating easily into the usual brand appearance.

This peel-off label allows reliable identification of unmarked syringes after refilling injection solutions

Reliable self-medication and user comfort

		User safety and comfort is the primary concern in the development of pens and autoinjectors for self-injection. Multi-functional label solutions can be individually customized to further enhance reliability and ease of use of these injection devices. The range of functionalities that can be realized includes a temperature indicator producing a reversible color shift that shows when a defined room or cooling temperature has been reached. A special varnish coating improves grip and feel of the surface and helps patients to safely use the pen. In addition, integrated tactile elements make it easier to tell apart similar systems containing different active ingredients through touch.

		If the pen has a transparent window to check the medication, the contents can be protected against UV rays by a double-layered label which can be easily opened and closed again. Alternatively, the transparent window included in the label can be equipped with UV protection.

Articles

Advanced label technologies serve functions far beyond product identification

The role of labels in patient safety

Injectable drugs represent many challenges to the healthcare delivery system: They are often handled by more than one person prior to administration (a pharmacist and a nurse, for example); sometimes the dosage must be measured out carefully (adjust for patient weight); and sometimes they are compounded or reconstituted. Some pharma manufacturers have responded to these challenges by making use of prefilled syringes or pens, which have the potential for patient self-administration. Now the industry should pay closer attention to how the drug labeling can provide similar advantages. 

Conversion of vials to prefilled syringes in various therapeutic categories, most notably vaccines and biotech drugs, was one of the most prominent changes in parenteral drug packaging in the past decade. The annual sales volume for prefilled syringes worldwide reached $33 billion in U.S. dollars in 2006. [1] Forward-thinking pharmaceutical marketers and packaging professionals reaped a series of benefits from offering their products in prefills and becoming part of this industry trend. Not only did they provide healthcare professionals with something that they valued in their practice, but they also effectively differentiated and advanced their own brands. Not quite a new indication, but well worth taking advantage of. 

Of course, the transition from a vial to a prefilled syringe is not an easy task that could be accomplished quickly or without risk. Changing the primary packaging for a parenteral is typically a challenging project, with extensive commitments both in terms of people and capital. For marketers of parenteral products pondering what alternatives they have for their product presentation improvements and brand differentiation, there is a clear and easy choice that nurses and hospital pharmacists really care about — labels with removable sections - or peel-offs as they are more commonly known. 

A label, in its simplest form, is only a printed sheet or film glued to the primary packaging of a pharmaceutical, providing basic identification information. A functional label adds more purposes beyond identification—such as for conveying recordkeeping or warning information. Peel-off labels (hereafter, POLs) feature two or more layers to the label, so that the same information on one label (in a typical application) can be peeled off and stored elsewhere (such as in a patient record). Not all POLs are ideal functional labels: Health care personnel might not understand the functionality at once, since it is not obvious or easy to use, or the functionality might not work properly due to the used material. But for cases where a functional goal is being met perfectly, POLs provide the opportunity to enter additional data (such as date of reconstitution or administration, or the preparer’s name, or the amount of drug administered). Different objectives are usually sought for POLs on single-use vials versus syringes. 

The key is that POLs can be customized to meet a variety of goals in patient safety and administration. 

According to market research conducted by Schreiner MediPharm (Blauvelt, NY), POLs are very likely to provide a marketing boost for vaccines, bloodborne pathogen products, anti-thrombotics, and many other injectable drugs and, in turn, deliver growth to the bottom line. The key is providing end-users with simple product features that they really care about. 

	The study included 761 respondents that participated in one-on-one personal interviews over a seven-month period. The study was conducted in three groups of end-users — nurses, pharmacists, and pediatric nurses. While the work environment and experience of the respondents varied from small practices to hospitals and from 5 – 25 years, all participants strongly preferred the POLs and highlighted the following benefits: 

POLs help reduce the potential for medication error. 

A clear majority have encountered patient records that are difficult to read and over half of the respondents believed that documentation errors occur (Fig. 1). Published reports support these findings. Medication error is the most common type of error affecting patient safety, occurring most often at points of transition in care—on admission to a hospital, at transfer from one department to another (such as from critical care to general care), and at discharge home or to another facility. The principal cause of medication error at such times is the incorrect or incomplete transfer of medication information. [2] A report by the Institute of Medicine estimates that as many as 44,000 to 98,000 people die in U.S. hospitals each year as the result of medical errors. [3] 

The respondents indicated that paper documentation for patient medications is still widely used in all healthcare facilities, now also often in conjunction with computer documentation. They enter the date of administering the drug as well as the drug’s name, batch number and expiry date of the medication in the patient’s medical records. Introducing a pre-printed, removable label with the clear identification of the drug or vaccine and variable data pertaining to the drug would be a major improvement to this process; over 90% of nurses and pharmacists found the POLs easy to implement and use in their daily practice (Fig. 2). 

An additional application of POL labels is when a medication is transferred after reconstitution from the original primary packaging into a different delivery device, such as a syringe or a mini-bag. Here, the peel-off section can provide clear evidence of the medication being delivered. This would also be the case if a drug is prepared in the hospital pharmacy and is then sent without the original vial to the floor for treatment. As part of the survey, 83% of the hospital pharmacists indicated that they re-label medications. 

As in other industries, the investigation of the downstream process chain (health care personnel) will increase in importance. It is of great value for pharmaceutical and biotech manufacturers to properly understand which benefits can be produced by intelligent labeling in order to improve the overall process quality of drug administration and documentation. Expert interviews show that healthcare professionals would prefer POLs. 

	While both nurses and pharmacists stated their strong preferences for POLs, the study also revealed that the current awareness of products with POLs is low. This creates a unique opportunity for savvy marketers interested in an innovative way of securing or improving their product positioning. Enhancing a prefill or vial with an end-user-preferred POL would result, by definition, in clear and obvious product differentiation - developing unique product differences with the intent to influence demand and the consumer perception of a product compared to its competition. It could also elevate a drug’s acceptance by its end-users. 

As Fig. 2 demonstrates, both nurses and pharmacists prefer POLs and would recommend them in their healthcare facilities. In fact, pharmacists specified 503 drugs and 216 vaccines they would like to see with the POLs. Vaccines, in both adult and pediatric applications, dominate the wish list and include, among others, Hepatitis A and B, influenza, tetanus, pneumococcal, and DTP vaccines. Antibiotics and blood products were also frequently mentioned. High-alert medications are another field of improvement for sophisticated label solutions. 

The very visible and obvious benefits of functional labels correlate to the high end-user approval ratings. These high-end labels that are typically made of modern mylar-type materials, can also make a clear statement about quality, especially when compared to simple paper labels perhaps being used by competitive medications. 

The healthcare professionals’ endorsement of POLs in 2004 mirrors that of the prefills in the 1990s in the U.S. Studies conducted at that time demonstrated that end-users preferred prefills. Meanwhile the U.S. is the biggest market for prefilled systems with a strong and growing prefilled syringes sector, which showed a growth rate of 9.7% from 2005 to 2006. POLs could easily be the next packaging improvement anticipated by the end-users but implemented with much greater simplicity by the pharma and biotech companies. 

	Of course, the pharmaceutical marketers must also be concerned about keeping their operational teams happy. Upgrading a parenteral drug with a functional label is basically quick and easy to do. 

From a manufacturing perspective, labels with peel-off features will run on existing labeling equipment with possibly only minor modifications. The regulatory requirements are equally easy to handle, as such a packaging change is not subject to pre-approval. From a cost perspective, functional labels are possibly the least expensive way to upgrade a medication. For example, moving from vials to prefilled syringes can easily produce more than three times the packaging cost per dose, while functional labels, which might add 5 cents per dose, are in comparison very economical. Besides, it has to be considered that health care personnel will use auxiliary labels to ensure that no unlabeled syringe or bag will reach a patient’s bedside. It has to be taken into account that this process also implies relevant costs for acquisition and administration. 

Manufacturing changes to consider mostly involve what additional information (such as item-level identification) are to be added, or the process of printing lot or expiry information multiple times on the label layers. POLs can be designed with a combination of adhesive layers and silicone-based release agents to provide convenient usage processes.

	Counterfeiting and authenticity have been of increasing concern in the pharmaceutical industry. Functional labels such as POLs can go a long way in providing a major barrier against counterfeiters because of the label’s complex build-up and manufacturing process. A label with peel-off features is typically comprised of multiple material layers and involves advanced silicone printing technologies, which if not performed well, will be very apparent to end-users as a peel-off feature that doesn’t work. 

	POLs are not new, but their application in Europe is in advance of U.S. applications. The earliest POLs (in Europe) were for handling pathogen-borne tissue samples and military applications. The technology received a boost from use in anesthetics, where the safety value was so pronounced that it is now required in most European markets. Recently, the U.K.’s National Health Service has recommended the use of POLs on all injectable drugs.

	Given these trends, it is easy to envision that pharmacy directors at healthcare facilities concerned with minimizing the risks of medication errors will come to prefer POLs. 

Manufacturers that make use of the technology will be at a competitive advantage.

	Based on market surveys, POLs are preferred by the end-users and, in their opinion, much needed in both acute and alternate settings. Combined with the nominal cost of incorporating a POL into the drug packaging and its transparency to a pharmaceutical company manufacturing process and regulatory filings, POLs represent a unique opportunity for packaging experts and marketing professionals. PC 

	2 Medication Reconciliation: Transfer of medication information across settings—keeping it free from error Jane H. Barnsteiner, PhD, RN, FAAN AJN, American Journal of Nursing, March 2005, Volume 105, Number 3 - Supplement: State of the Science on Safe Medication Administration Pages 31 — 36.

	3 20 Tips to Help Prevent Medical Errors. Patient Fact Sheet. AHRQ Publication No. 00-PO38, February 2000. Agency for Healthcare Research and Quality, Rockville, MD. 

Peter Seidl is Director, Technical Support at Schreiner MediPharm, a division of Munich-based Schreiner Group. Schreiner MediPharm specializes in marking technologies and self-adhesive functional solutions for the pharmaceutical industry and has global activities including a US manufacturing location in Blauvelt, NY. Peter Seidl has extensive experience in developing multi-functional labeling solutions with value-added benefits tailored to the specific requirements of the pharma industry. 

Functional (“peel-off”) labels, common in Europe for injectables, represent a significant packaging improvement for safer and more efficient drug administration