Wednesday, June 10, 2009

Pharmaceutical Labeling

Tough regulations, high standards and utmost quality set drug labels — and their converters — apart from the rest.

Labeling pharmaceutical products poses challenges to converters unlike those encountered in other industries because of the regulations in place to ensure their accuracy. In addition to making sure the labels are correct, converters might be asked to implement anti-counterfeiting measures to protect both consumers against dangerous counterfeits and pharmaceutical companies that make legitimate products.

Staying ahead of counterfeiters is one area of pharmaceutical labeling that gets constant attention. Michael Brady, president and owner of HP Mile, a company that produces labels for the pharmaceutical and biotech industries in Syracuse, NY, USA, explains: “The newest techniques used in pharmaceutical labeling have been introduced to battle counterfeiting and mix-ups. These techniques are designed to protect the consumer and ensure the integrity of the pharmaceutical product. These range from unit-of-use bar coding to RFID tagging. Some techniques in between are use of holograms, pattern adhesives or even serial numbers printed on the label with invisible varnish or ink.”

Extended content and resealable labels have been put into more widespread use. Nick Van Alstine, president of Macaran Printed Products, a converter in Cohoes, NY, that produces over-the-counter and prescription labels, says, “Due to regulatory requirements pertaining to patient information, many pharmaceutical labels have needed to move to extended content or resealable labels to accommodate all of the information that is required to stay with the product.” He explains, “A resealable label is one that opens like a book with pages of information to be read. Once opened, the label can then be closed and sealed again. Another method is to use the booklet style, where the information folds out accordion-like.”

Another new development is with bar codes. Van Alstine says, “Recently we have seen a move towards using data matrix bar codes. A data matrix code is a two-dimensional matrix bar code that can be encoded with large amounts of either text or raw data. This type of code is popular for marking small items, due to the code’s ability to encode up to 50 characters in a symbol that is readable at very small sizes.”

Robert Delaney, quality assurance manager at Logotech, a converter in Fairfield, NJ, USA, says that materials are the components of pharmaceutical labeling that have changed the most. “Not much has changed in the printing aspect; the machines used years ago are still some of the best out there. The uses of different materials such as face sheets, inks and varnishes have changed dramatically in the past few years as technology has advanced.”

According to Lou Thurston, senior label business development manager at Corporate Express Document & Print Management, a company in Wichita, KS, USA that provides paper and film labels for prescription and over-the-counter products, there has been a “migration from paper labels to film — from screen print to UV letterpress and UV flexo printing — and requirements for 100 percent verification of readable bar codes.”

Shari Dause is director of marketing at TimeMed Labeling Systems, a company in Burr Ridge, IL, USA that produces laser and thermal labels that are used for unit dose, intravenous bags, syringes, and patient prescription vials. She says, “In retail there is a strong movement towards thermal print technology based on automation and workflow software changes. Security ink systems also are being used at repackaging facilities (mail order and central fill) to track, much like RFID, the movement of each lot.”

TimeMed focuses on labeling for healthcare providers. An example of that is a patient prescription label attached to the medication. Pharmex, a division of TimeMed, has worked with Innovation Associates Inc., a company involved with automated prescription dispensing, to produce customized thermal prescription vial labels for pharmacies. Innovation’s PharmASSIST products automatically apply labels to bottles in whatever quantities the pharmacist needs. Pharmex labels are placed onto the pharmaceutical bottles for the consumer.

Pharmex offers C2Rx for pharmaceutical labeling, which is designed to minimize the risk of fading and darkening of direct thermal prescription labels. C2Rx is also meant to withstand exposure to hand soaps or sanitizers, alcohol, common household products, and sunlight.


In order to ensure that pharmaceutical labels come out correctly, certain standards exist. Thurston says, “Total suite of GMPs (Good Manufacturing Practices) are in place to ensure line clearance, segregation products, 100 percent inspection of critical information, as well as the control and traceability of labels and materials throughout the process.”

HP Mile’s Brady says, “We have SOPs (Standard Operating Procedures) from order entry through shipping that have been audited and approved by many of the large pharmaceutical companies. We have redundant inspections both on press and after printing, and people who have been trained in cGMPs (current Good Manufacturing Processes), which help to ensure product quality.”

Procedures for verifying pharmaceutical labels can be quite involved. Van Alstine details Macaran’s process: “A formally documented set of pharmaceutical SOPs is in place to ensure that each step of the process, from order entry to shipment is done correctly. These procedures include a checklist document that follows each individual SKU as it moves through the process, department by department. A signature and date is required upon successful completion of each individual step by the person performing each task. In the pressroom, once all the steps are completed, the department supervisor double checks each step for accuracy and signs it off for processing to the next department. In addition, QC inspectors check randomly throughout the process and are required to give final approval before the order is shipped. Only one SKU at a time can be in process in a particular work cell. Segregation of each SKU is imperative to avoid label mix-up. The QC and regulatory departments of our pharmaceutical clients conduct auditing of our procedures from time to time. Macaran is also ISO 9001 certified.”

The Omega SR 1300 with the Flytec PharmaControl inspection system. Photo courtesy of HP Mile.
In addition to converters’ practices, governmental organizations such as the US Food and Drug Administration (FDA) have policies regulating pharmaceutical labels. The FDA updates its guidelines as it sees fit. For example, on January 24, 2006, according to the FDA’s web site, the organization “amend[ed] its regulations governing the content and format of labeling for human prescription drug products (including biological products that are regulated as drugs). The final rule revises current regulations to require that the labeling of new and recently approved products include highlights of prescribing information and a table of contents. The final rule also reorders certain sections, requires minor content changes, and sets minimum graphical requirements. These revisions will make it easier for health care practitioners to access, read and use information in prescription drug labeling.”

FDA policies for labels are specific. Van Alstine says, “The FDA regulates every aspect of a drug label including content and format. The CFR, or Code of Federal Regulations, spells out exactly what is required. Any new or changed label must be submitted along with supporting data for approval. This process can be quite lengthy. Most of the goals under the new labeling rules are for more informative and accessible labeling, better risk communication and fewer medication errors.”

Regulating content for pharmaceutical labels has helped change the labeling format. Delaney explains, “Because the FDA requires so much information to be passed on to the consumer — details on dose, safety, side effects, and other aspects of the medication — it’s opened up a tremendous market for extended content labels such as booklet labels, piggyback labels and other ways to fold a great deal of information into a small space.”

Stringent regulations from the FDA have also made inspection an essential part of pharmaceutical label production. According to Thurston, “Vision systems for 100 percent inspection of critical information such as bar codes, critical text, etc.” are the most common.

Brady says, “Electronic inspection and verification is what most label printers that are in the pharmaceutical arena are using. This is accomplished using a vision inspection system that uses electronic imaging technology to ensure precise and accurate inspection of labels. On our presses we have a digital inspection system that takes a snapshot of the moving web and displays real-time images on a high resolution monitor. This allows the operator to catch any misprints or registration issues and take corrective action.”

In addition to on press equipment, 100 percent inspection systems can be used on the rewinder after printing is complete to remove bad labels before they are sent to customers. [For a report about inspection equipment, see “Label Inspection” on page 40.]

Converters also need to comply with pharmaceutical companies’ requests when it comes to labeling their products. WellSpring Pharma, a pharmaceutical company located in Toronto, ON, Canada, qualifies its printers with an audit. Laura McClure, buyer, materials management for WellSpring, explains, “The audit includes a tour of the facility and review of SOPs, training records, validation records, calibration records, change control procedures, and the Deviation Reporting System. Certification of regulatory bodies is requested as well as the supplier’s organizational chart. Other documentation requested includes manufacturing processes, quality systems, lot control, pest control, specification and procedure issuance, internal audits, environmental monitoring, and record/sample retention.”

After the initial audit, WellSpring Pharma also conducts a surveillance audit every three years. McClure says, “A surveillance form is forwarded to the supplier for completion. This form covers any changes to the facility, updated establishment license, ISO or other regulatory body certifications. We review any change controls and/or non-conformance reports issued over the past three years. After completion of the form and review of documentation, the decision is made as to whether or not a visit to the facility is required.”

In addition to successfully completing audits, converters also must abide by pharmaceutical companies’ policies regarding label production. Shannon McBrien, QA coordinator at WellSpring Pharma, explains, “We provide an in-house specification which details our inventory code; complete label description; stock and adhesive type; Pantone colors; dimensions; container, handling and storage requirements; and retest and expiry dates if applicable. The artwork, i.e., approved proofs, and all details of the artwork changes are controlled via a separate change control docket system.”

Ethical vs. OTC

Ethical pharmaceuticals (ones that require a prescription from consumers) have stricter labeling guidelines than over-the-counter (OTC) medications. Van Alstine says, “The FD&C Act, or Food Drug & Cosmetic Act, separated prescription drugs from over-the-counter in 1951 with the Durham–Humphrey amendment.” The amendment gave the FDA the authority to decide which drugs required a prescription and which would be available as OTC. Previously, the decision was left up to the drug manufacturers.

Although there are differences in the regulations, many converters use the stronger guidelines for both ethical and OTC products. Van Alstine says Macaran uses the same standards for both, as does HP Mile’s Brady. Brady adds, however, “One difference is that in low cost over-the-counter drugs, i.e., 100 count aspirin tablets, the anti-counterfeiting aspect is not as much of a concern typically due to the lower dollar value.”

RFID and anti-counterfeiting techniques

RFID is a topic of discussion in the pharmaceutical industry because of its security features. Currently, however, use of RFID isn’t widespread. Van Alstine says, “RFID is not substantially used as a measure of security in pharmaceutical labeling. The high cost of implementation and lack of a proper infrastructure to support it has been a barrier to this technology so far. There has been talk of developing a ‘pedigree’ for prescription drugs, which would likely include RFID as a way of providing a tracking history throughout the life of the product. This is still down the road.”

According to Thurston, “RFID is emerging primarily as a traceability solution in the pharmaceutical industry and helps provide some elements of security. It is not prevalent across the industry yet. Early adopters have implemented it on some high risk products, but it has not been accepted as an industry-wide solution due to the cost of RFID and the infrastructure to access the information.”

Delaney agrees that the technology can be expensive. He says, however, “Pharmaceutical companies face counterfeiting of products on a daily basis, so security technologies are becoming increasingly important even though the costs are high. Acquiring a specialist in security features is the next trend in printing.”

Brady is optimistic that RFID will become more common. “The use of RFID in pharmaceuticals is gaining prevalence to combat counterfeit and compromised drugs. As the cost of implementing an RFID program continues to fall and the reliability continues to increase, you will begin to see it used more and more on high-counterfeit products.”

Other security measures exist to prevent counterfeiting. Overt, covert and forensic techniques can all be employed to thwart counterfeiters. Dause says, “Security inks and adhesives, security or tamper evident material and security printing are all examples of processes and material selections that converters may offer to manufacturers and system integrators as a means to register and track the pedigree of the drug.”

Delaney explains more complex methods: “There are a host of vendors offering materials impregnated with items such as taggants or special threads only detected under special lighting or laminated with computer chips. There are also a plethora of ink manufacturers that offer special inks not visible to the naked eye; printing techniques that are called micro printing, printing so small you need a loupe to view printing. In combination with the micro printing and the special florescent inks, it is very difficult for counterfeiters to duplicate the printing process.”

Different bar codes can provide additional security. Van Alstine says, “One thing that converters can readily offer is the ability to print data matrix codes. The code and accompanying alphanumeric data can be used to identify details of the product, such as components, including manufacturer ID, part number and a unique serial number. Other solutions are available; but until an infrastructure exists that can support verification throughout the entire supply chain, one has to question how effective they can be.”

A higher cost

Pharmaceutical labels are more expensive than those used on other products because of the additional steps needed to ensure accuracy. Logotech’s Delaney says, “Pharmaceutical labels really do cost more because of the cGMPs, SOPs and AQLs (Acceptable Quality Levels) we have to follow in order to produce a product suitable for the pharmaceutical industry.”

Brady says, “The additional steps to ensure 100 percent accurate labels for the pharmaceutical industry add to the cost structure.” He adds that HP Mile has implemented Lean Manufacturing processes to help reduce the costs. Those cost savings are passed on to customers.

Thurston, of Corporate Express, says, “Pharmaceutical labels are higher in cost primarily as a result of the additional costs in manufacturing due to segregation, traceability and security requirements. You cannot ‘gang’ run pharmaceutical labels that require strict line clearance between label kinds.”

Pharmaceutical companies may put price below other components when choosing a converter. At WellSpring Pharma, McClure ranks price below both quality and service. She explains, “Poor quality costs money due to possible downtime, potential back-order situations, rejection issuance, etc., which you cannot put a price on. Service from the supplier is equally important, i.e. on time deliveries, response time to artwork changes and documentation required by WPCC QA [WellSpring Pharmaceutical Corporation Canada Quality Assurance] or our customers must be forwarded in a timely manner.”

The extra cost is worth it when taking into consideration what the consequences of defects can be. Delaney points out, “Medications, especially prescription medications, deal with people’s health and well being, so a simple thing such as a decimal point in the wrong place, a speck of dust on the printing plate or a smudge on the label can mean the difference between a full recovery of the patient or death of the patient.”

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