Labels & Package Content Continue to Attract Regulatory Focus

What keeps the pharma industry from getting its patient-safety message right?


No matter what innovative, potent or life-saving drug is being delivered to a patient by a pharmacist, it is worth nothing unless its labeling is accurate, available and approved. This seemingly small packaging detail continually trips up manufacturers, who are required to recall erroneous labeling and package inserts, either by FDA mandate, or as a precautionary measure to avoid liability suits. Moreover, the ferocious debates among medical regulators and industry over side effects of many drugs are functionally resolved by including a new or revised “black box” warning on the label.


All this highlights the care (and expense) that the industry devotes to labels and package inserts (PIs). Packaging and printing service providers to the industry have responded by expanding the range of materials, features and options for conveying labeling information. “There are a number of new packaging solutions developed by the pharma industry which are gaining traction,” observes Narendra Srivatsa, business development manager at Cortegra, a provider of cGMP compliant packaging and labeling services. “There’s an increased emphasis to reduce medication errors and include more information.”

Problems with medication errors are well documented and estimated to cause 7,000 deaths annually in the United States (and nearly 100,000 for overall medical errors), according to the landmark Institute of Medicine 1999 report, “To Err is Human.” Meanwhile, high workloads for pharmacists increase the potential for medication errors, according to a new study by the University of Arizona College of Pharmacy (Tucson, AZ). Further compounding matters are patient challenges in self-administration, which are numerous and include complex regiments, poor patient education and literacy.

“The use of a nondescript bottle and vial packaging can compound these issues with small font sizes, non-distinguished colors and an inability to link key information, such as dosing reminders or titration schedules to the package,” notes Eric Masters, senior strategic marketing manager at packaging designer MeadWestvaco (MWV; Glen Allen, VA). “These issues are widespread as more than 32 million Americans currently take three or more medications per day and over half of senior citizens take five or more medications per day.”

New labeling laws enacted by FDA over the past two years were aimed at forcing pharma companies to capture a physician’s attention to the most important pieces of drug information before a product is prescribed. Among the most significant changes was requiring drug makers, for the first time, to submit prescribing and product information to FDA – such as a package insert (PI) or label—in a Structured Product Labeling (SPL) format, and to update PIs annually. SPL is designed to provide accurate, specific information using standardized medical terminology in a readable, accessible format.

“Although the principal audience for the new labeling requirements is the healthcare professional, several of the revisions have an impact on patients,” says Karen Mahoney, an FDA spokesperson. “One improvement is that the new labeling emphasizes the importance of counseling patients about their prescription drugs by including a new section called ‘Patient Counseling Information.’”

PIs are used in numerous ways by healthcare providers, including pharmacies that receive and dispense drugs, and provide important information for the safe and effective use of the product.

If a drug has an FDA-approved PI, it will be printed at the end of the labeling immediately following the Patient Counseling Information section, or accompany the labeling so it can be easily shared. “Some drugs, by regulation, are required to have patient package inserts which must be distributed to patients,” Mahoney explains. “Drugs that FDA determines pose a serious and significant public health concern are required to have FDA-approved Medication Guides that are distributed to patients.”

By providing accurate and readable information with Medication Guides, pharma companies can help educate and involve patients in their care. “There is nothing like a solid understanding of not only the benefits of drugs, but also the risks to support patient safety and drug effectiveness,” says Tom Henderson, VP, sales and marketing, North America, Chesapeake Pharmaceutical Packaging North America (Lake Success, NY), who serves on the executive committee of the Pharmaceutical Printed Literature Association (Batavia, IL).

Impact of Revamped Labeling Regs
“The goal of the initiatives involving SPL is to improve the safe use of drugs by increasing access to up-to-date drug product information,” says Crystal Rice, an FDA spokesperson. “This is a collaboration between the drug companies, FDA, NLM and drug information suppliers.”

Using embedded computer tags, prescribing and product information in the SPL format can be electronically managed, allowing a user to search for specific data. These tags can instruct computers to read specific sections of a drug label such as indications, dosage and administration, and warnings.
In response to the industry’s expanded use of larger printed material and recent FDA regulations on labeling, printers say have increased paper panel sizes to enable pharma companies to put more useful information on leaflets and print in larger type sizes. “What FDA has done is create a four- or five-year schedule by which drug manufacturers switch over to the SPL format,” Cortegra’s Srivatsa notes. “This has changed the size of packaging and promoted the use of large format inserts.” Cortegra offers wide-format folding capabilities for inserts and outserts.

Meanwhile, carton and label providers say they are working on keeping inserts and outserts to manageable sizes. The latest products provide space to accommodate more useful information while removing some obstacles that the additional components might create on packaging lines. “We accomplish this by providing combinations of printed components into a single packaging item,” explains Gregg Metcalf, industry market manager, Nosco Security Protection and Nosco RFID Package Integration (Waukegan, IL).

“For example, a patient compliance leaflet could be attached to a folding carton or to a pressure sensitive label,” Metcalf says. “A single package is delivered to the production line but contains pre-attached patient compliance information.”

One of the advantages of delivering pharmaceuticals in blister cards is that there is simply more space, both on the card and on the container or carton that holds it. These forms of “compliance packaging” can provide additional features, such as a graphic for daily, weekly or monthly prescription regimens, thus reminding patients when to take their meds. Another definition is “pass through” packaging, in that it stays intact from the manufacturer, to the pharmacist, to the patient, unlike the conventional practice of counting out pills and putting them in an amber bottle at the pharmacy. “For pharmacies, pass-through packaging can significantly reduce the workload by eliminating counting and providing well-labeled, easy-to-identify medications,” MWV’s Masters says. “Many retailers are now asking generic and branded manufacturers to consider pass-through packaging for these reasons.”

Two of MWV recently introduced products, Shellpak and Dosepak Express, provide calendared blisters which help remind consumers to take their meds, or if they have already taken their necessary dose, thus reducing overdosing issues. “Using labels on both sides of the Shellpak package maximizes the amount of information that can be delivered to the consumer and the font sizes that can be used, thus reducing the risk for confusion or user error,” Masters says. Dosepak Express provides substantial information through the paperboard package as well as a pocket which can hold the patient insert or other important information.

Barcoding Technology Benefits Touted
A technology which holds the promise of driving life-saving innovation to drug labeling is barcode-enabled medication administration (BCMA). BCMA is used to verify all medications electronically before they are administered to patients.

“For BCMA systems to be effective, pharmacists must be involved in all phases, from technology selection through implementation” stated past ASHP president Kevin Colgan. In April, ASHP published a statement encouraging hospitals and health systems to adopt BCMA technology in all areas of medication use.
Healthcare providers who have implemented barcoding solutions found improved patient safety through the reduction of preventable medication errors. For example, First DataBank (South San Francisco, CA) recently sponsored a webinar that reported on two hospital systems — Maimonides Medical Center (Brooklyn, NY) and Southern Ohio Medical Center (Portsmouth, OH) —who successfully implemented barcode technology in the pharmacy system and at the patient bedside through the use of an electronic medication administration (eMAR) system.

“Our goal in this webinar was to highlight how First DataBank’s drug databases are used in barcoding applications within hospitals, can help prevent medication errors both in the pharmacy and at the bedside,” says Denise Apcar, a First DataBank spokesperson. The firm provides drug databases used within healthcare information systems.

Despite the energy surrounding barcoding, implementation is moving at a snail’s pace. According to a statement encouraging use of BCMA published by ASHP in April, roughly a quarter of US hospitals have implemented some form of BCMA. That’s almost double what it was in 2005, when FDA first mandated the use of barcodes on pharmaceutical packages delivered to hospitals. This slow progress is all the more disheartening in that it is well documented that BCMA saves lives and reduces liability for hospitals. Part of the holdup comes from the physician element of the process: Computerized physician order entry (CPOE), which enables physicians to record prescriptions electronically and then transmit the prescription to the hospital pharmacy, is in use by only 17% of hospitals, according to a 2008 survey by KLAS Enterprises (Orem UT), a market research firm. BCMA together with CPOE are the main component of “closed loop medication administration,” which would digitize the entire prescribing dispensing and administering of pharmaceuticals.

Hospitals and health systems are being urged by professional societies and other entities to allocate necessary funding and personnel to maintain the planning, development, and management of BCMA systems. “Hospitals are not working with barcoded labels as much as they really should be,” Cortegra’s Srivatsa concurs. “When companies see cost savings attached to a particular solution, they tend to implement it sooner.”

Peel-off Labels
The drive to cram ever-more information onto labels has been addressed by label converters through the use of “extended content” labels, which in effect allow for a multipage-pamphlet or booklet to be physically attached to the label. Variations include “multi-ply” labels (with 2-5 labels stacked on top of each other), “peel off” labels, or multi-part labels with, for example, a set of copies of the product’s barcode included in the label.

Many pharma label converters offer these products; companies that list specific variations in their product literature include CCL Label (Hightstown, NJ), Cortegra, Challenge Printing Co., Chesapeake, Nosco and National Label Co. (Lafayette Hill, PA), and Schreiner MediPharm (Blauvelt, NY), among others.
“Combined with the nominal cost of incorporating a peel-off label 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,” says Peter Seidl, director of technical support at Schreiner MediPharm.

Featuring two or more layers, POLs enable the same information on one label for a typical application to be peeled off and stored elsewhere, such as in a patient record. 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 and amount of drug administered. “Different objectives are usually sought for POLs on single-use vials versus syringes,” Seidl says. “The key is that POLs can be customized to meet a variety of goals in patient safety and administration.”

POLs serve a dual purpose 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,” Seidl says.

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,” Seidl says.

Although fairly common in European hospitals, POLs and other enhanced labels have a two strikes against them in the US: pharma companies feel no particular pressure to produce a label specifically for hospital use (even though ASHP, in its April statement on prescribing, recommends this) and only a fraction of hospitals today are equipped to make use of them.

Product Lifecycle Management
Product and dosing instructions presented on the Rx drug label not only need to be accurate, but traceable to the point of origin in event of a recall. A case in point involves anti-depressant drugs, which have been linked to suicidal thoughts and behavior in young adults. Since their recall, FDA enforced that all anti-depressant drug makers update the existing black box warning on their products’ labeling to include details on such increased risks during initial treatment.

“Makers of well-known drugs like Plavix, Paxil, Prozac and Celexa had to scramble to pull their drugs off the shelf and re-label,” reports Jean Colombel, director of life sciences industry strategy for Dassault Systèmes (Lowell, MA).

There is progress being made to develop solutions which enable pharma companies to consistently achieve targeted results and comply with regulatory requirements. One solution is called Product Lifecycle Management (PLM), a system enabling vendors to monitor and manage the labeling process worldwide from a central repository. According to Colombel, PLM assists in handling the design, review, approval, printing and reconciliation requirements in a secure manner with extensive audit trails and reporting capabilities.

To answer this need and provide a comprehensive “single source of truth” for drug labeling information, Dassault Systèmes has deployed a solution based on its Enovia V6 PLM platform. “A number of large and mid-size pharmaceutical companies have dramatically reduced the risk of mixing errors between approved and published artworks,” says Jean Colombel, director life sciences industry at Dassault.
As the healthcare system advances into the 21st century, FDA is considering how dissemination of the prescribing information contained in the PI can take advantage of technological advances in the electronic transmission of information. While errors can occur at any point in the medication process, the last point to catch the error before it reaches the patient is at the time of administration. “Regulated labeling requires human collaboration from multiple departments within the pharmaceutical company, as well as with artwork agencies and local country representatives,” Colombel says, suggesting quality assurance and control, regulatory affairs, legal and marketing groups all need to be involved. “The goals and objectives for each internal or external participant rarely align and the process of managing regulated labeling continues to be a challenge.” PC

Automating Proofreading Found to Improve Accuracy of Packaging Components

Traditionally, the proofreading of the artwork and text on a pharmaceutical package has been done manually. This may have been a good idea at some point in the past, but today, with the same pharmaceutical contained in multiple stock-keeping units (SKUs), and with multiple foreign-language requirements, proofing one brand’s packaging can take hundreds of hours. Add in the last-minute changes commonly generated during the FDA review process, and the task can add weeks to a product launch date. Further, the evidence is readily at hand that industry is not managing this process well: every year, hundreds of product recalls occur because of text and artwork errors on packaging.
Enter automated proofreading. According to Kim Quelch, a spokesperson for Global Vision (Montreal), a provider of automated proofreading solutions, the technology eliminates uncertainties common with a manual proofreading system. It can be applied at various stages of the workflow process to ensure complete accuracy. “Automated proofreading solutions use advanced artwork and text verification technology to protect the integrity of all artwork and textual components, centralize inspections and allow for early detection of errors,” Quelch says. “They enable the user to verify any differences between two files by comparing a sample to an authorized master.” The system can evaluate and detect differences in electronic files to printed components and electronic files to electronic files.

Catalent Pharma Solutions (Somerset, NJ), providers of manufacturing and packaging services to the pharma industry, reportedly used to operate by means of manual verification to approve samples off the press. When it switched over to automated proofreading solutions, the benefits were twofold. “They were able to assure their customers that their materials were being properly looked after and consequently developed stronger relationships with them,” Quelch says. “Secondly, they were able to decrease their costs and improve employee productivity.”

Paxonix (New York), a business unit of MeadWestvaco, has partnered with Global Vision to make the latter’s Docu-Proof a component of PaxPro, its packaging-design workflow and data-management system. PC
—F.J. Quinn