One drug packaging consultant doesn’t mince words in describing how drug manufacturers would be affected if the Food and Drug Administration (FDA) requires them to serialize their drug packages. “The [stuff] will hit the fan,” said this long-term industry advisor who has worked extensively with GS1 Healthcare, the industry standards group that has approved a number of drug packaging data standards, including GS1 DataMatrix, designed for tiny, two-dimensional (2D) barcodes that can fit on unit-of-use drug packages as small as ampules. 

The possibility of a serialization edict has come into play because the FDA announced last October 26 that it is considering changes to its 2004 pharmaceutical package barcode rule, which requires manufacturers to put a linear barcode with the National Drug Code of the product on most unit of use packages. The reconsideration stems in part from an Executive Order signed by President Obama on February 2, 2011. It requires federal regulatory agencies to consider strengthening, complementing or modernizing rules where necessary or appropriate. The FDA said it chose the barcode rule as the first one to focus on. The agency plans to reassess the costs and benefits of the 2004 rule to determine if it should be modified to take into account availability of new technology.

The FDA imposed the linear barcode requirement, which went into effect in 2006, primarily as a result of a report from the Institute of Medicine five years earlier. The report was called To Err is Human. . .  and said preventable adverse events caused “at least 44,000 and perhaps as many as 98,000 deaths in hospitals each year.” The report cited hospital patients receiving the wrong drug, sometimes because of confusion where two drugs had similar names, sometimes because of outright hospital employee carelessness and sometimes for other reasons. Linear barcodes were seen as a way to reduce hospital medication errors.

Medication errors in hospitals are still a concern, but over the past five years, the FDA has become alarmed by the invasion of counterfeit drugs into the legitimate U.S. pharmaceutical distribution system. Finding those leaks requires “tracking and tracing” of drug products from when they leave a manufacturer’s production line to when they arrive at a retail or hospital pharmacy. That cannot be done with linear barcodes; they simply do not support the requisite automation. Requiring manufacturers to print serialized GS1 DataMatrix barcodes — the standard for which only recently became available — would allow track and trace.

The discovery of counterfeit Avastin in U.S. pharmacies in February 2012 probably pushed Congress and/or the FDA even closer to a serialization decree. Avastin is a widely-prescribed cancer therapy. Avastin has six-digit lot number printed on the container, but not within the linear barcode. Lot numbers and expiration dates can be printed in 2D DataMatrix codes, making it easier for companies to track and trace legitimate product and identify counterfeit product. Serialization makes tracking and tracing even easier. Not only does it reduce the chance of “bad product” reaching consumers, it also reduces the time it takes to get recalled products back, and cuts a pharmacy’s costs in complying with a recall. 

Reducing recall and liability costs and addressing a looming 2015 California deadline to serialize drug pakcages are two of the main reasons drug manufacturers are pressuring the FDA to modernize the 2004 rule. Manufacturers want the FDA to set a single national, drug tracking standard rather than being forced to comply with California’s e-Pedigree standard, and possibly 49 other, potentially different state standards. An e-Pedigree requires a package to have a unique serial number in addition to other information, such as the lot number and expiration date. Those latter two bits of information are today printed separately on a drug package, outside the linear barcode, which only contains a drug’s National Drug Code (NDC). If the NDC were serialized within a linear barcode, the package would have to be as wide as a “before” contestant on The Biggest Loser.  A GS1 DataMatrix barcode can fit on the smallest of containers, and can easily accommodate a serial number.

The FDA might need congressional approval to requiring serialization, but that may be forthcoming as legislators reauthorize the Prescription Drug Users Fee Act (PDUFA). The 2007 version of PDUFA included a requirement that the FDA publish industry guidance on how manufacturers could use a Standardized Numerical Indentifier (SNI) on a drug package. That was seen as the first step toward pharmaceutical package serialization. Kendra Martello, assistant general counsel for the Pharmaceutical Research and Manufacturers of America (PhRMA), argued that the FDA should drop the linear requirement entirely by 2016. “After 2016, only 2D barcodes should be used, consistent with manufacturers’ migration to the use of 2D barcodes for other applications,” she stated. 

The shift by manufacturers from printing linear barcodes to printing serialized, 2D DataMatrix barcodes (whether using the GS1 standard or some other standard) will entail major investments on packaging lines. Brajinder Singh is an associate partner with Clarkston Consulting, which is working with drug manufacturers to think through the steps they will have to take to serialize drug packages. “While some companies have already started down the serialization path, most companies are just beginning to stick their toes in the water,” he said, meaning they haven’t gotten much further than evaluating how they want to move forward. Mr. Singh noted that serialization will force packagers not simply to upgrade Manufacturing Execution Systems (MES) supplied by the likes of Werum, Systech and others, but to integrate new hardware and software with serialization and traceability and back office Enterprise Resource Planning (ERP) systems, responsible for managing serial numbers and business data sent to the packaging line. “In addition, it is also a significant investment to validate the packaging line, beyond process and equipment validation,” said Mr. Singh.

Aside from the fact they can include much more information in a tiny barcode, 2D DataMatrix barcodes are easier to read and have error correction capabilities, advantages which accrue to end-users as well as manufacturers. However, when 2D barcodes are serialized, a manufacturer’s costs spike suddenly and considerably, since the barcodes have to be printed one at a time, as each container or blister pack moves down the packaging line. Then those container-level barcodes have to be linked to the “mother” cartons they are placed in and the “grandmother” pallets the cartons are stored on as they leave the plant. That requires considerable packaging line auditing and verification, as well as coordination with back office software, where serial numbers are selected and then passed down to the packaging line for printing. 

The FDA has already cracked open the 2D door. It allowed vaccine vendors to start using 2D barcodes alone in 2011. Vaccines are a special case because of the National Childhood Vaccine Injury Act of 1986, which requires healthcare providers to report certain adverse events related to identified childhood vaccines to the Vaccine Adverse Event Reporting System. Sanofi Pasteur is printing GS1 DataMatrix codes on pediatric diphtheria and tetanus toxoids adsorbed vaccine, according to press reports. Amy Ba, a Sanofi spokeswoman, said the packages are not serialized, however. 

GS1 is the international standards group whose healthcare component has been working on pharmaceutical product tagging standards. The GS1 DataMatrix standard was not available in 2004, when the FDA finalized its barcode rule. “For the past three years, many pharmaceutical manufacturers have implemented GS1 DataMatrix in response to the California Pedigree and FDA SNI guidance,” said Mark J. Goldberger M.D., M.P.H., divisional vice president, Regulatory Policy & Intelligence, Abbott Laboratories. “Globally, GS1 DataMatrix is the preferred data carrier for encoding variable data on the unit of sale due to the small size of the data carrier.” The reference to SNI guidance has to do with FDA publication in 2010 of guidelines for printing a Serialized Numerical Identifier (SNI) on drug packages as the first step toward serialization. But only a miniscule number of drug packages reaching hospital and retail pharmacies today are serialized. That guidance had almost no impact on the industry.

So Mr. Goldberger painted a rosier picture than reality dictates. Very few companies are printing GS1 DataMatrix barcodes on products destined for U.S. markets. Even fewer are serializing product, either with a GS1 DataMatrix barcode or a GS1 DataBar barcode. Here is the situation vis-a-vis drug packaging today. The vast majority of prescription drug manufacturers use a linear barcode that contains a National Drug Code. The linear barcode restricts information to product identification only and does not provide enough granular information for tracing the product through the supply chain. Additional production information is required for authentication or tracking or tracing.

A tiny number of manufacturers use a GS1 DataBar code, which is a small stack of linear barcodes containing, in addition to the NDC, lot number and expiration date. Even more production and tracking information can be included in a GS1 DataMatrix barcode, which can include a serialized Global Trade Item Number (GTIN). There are only a small handful of U.S. companies printing serialized GS1 DataMatrix barcodes on drug products, and then only for selected products, most of them packaged overseas. 

The lack of GS1 DataMatrix adoption in the U.S. contrasts with its adoption in many other countries. DataMatrix (again, usually based on the global GS1 standard) is now required in Argentina, France, Turkey, Korea, and India. The European Commission’s Delegated Act On The Detailed Rules for a Unique Identifier for Medicinal Products for Human Use recommends the 2D DataMatrixbarcode. DataMatrix is also being used in pilots and/or developing as a requirement in Canada, Brazil, Spain, Switzerland, Belgium, Austria, and Serbia.

A transition from linear and GS1 DataBar codes to a serialized GS1-DataMatrix barcodes would require considerable and likely expensive changes on pharmaceutical packaging lines. Larger manufacturers with volumes of millions of containers will undoubtedly make the investments on their own lines. Clive Hohberger, managing director of Clive Hohberger, LLC, explained that serializing requires that a unique number be printed on a label as that label is affixed to a product on the packaging line or printed directly on the product itself. As things stand today, pre-printed unchanging linear barcodes are applied as a container travels down the packaging line. Current packaging line printers are not able to print a unique serial number at the rate of 150-500 per minute, which is the current rate of packaging line speed, with 500/per being a very upper limit. Not only will printers (either steerable laser or more likely high speed inkjet) have to be faster to print DataMatrix on the line, they will have to be able to print the smaller DataMatrix barcodes with reasonable accuracy.

Some suppliers offer a soup-to-nuts system. Robert Rack, president of RDG / BarCodeAmerica.com, said his company’s RDG 7000XR Rewinder system fully implements e-Pedigree using a 4K Line Scan Camera-based Vision System that inspects not only the expiration date and lot print but rather 100% of the label print, including all of the pre-printed label copy and text, and on top of that will provide true, accurate ISO grading of both standard barcode and serialized unique barcode.

Companies such as Systech Inter-national have packaging execution systems available that meet serialization and track and trace needs. “Pharmaceu-tical counterfeiting is a global problem that is growing rapidly,” noted Joe Ringwood, chief operating officer of Systech International. “In response, more countries like Brazil are legislating regulatory requirements that require item, case and pallet level serialization. Our serialization solution has been deployed worldwide by companies addressing various anti-counterfeiting requirements.”

Smaller pharmaceutical manufacturers may decide, because of the complexity of the conversion and the cost, to avail themselves of a contract packager. That is what Danco Labs did, according to Mr. Rack, who declined to name the contract packager involved. That is because there is a “security” concern given the drug involved is mifepristone, better known as RU-486 (the abortion pill). “We supplied the complete systems, code reading, turnkey software, audit trail, label printer-applicators, and operator training to make that happen,” Mr. Rack said. Mifepristone carries both 1D and serialized 2D DataMatrix labels on the primary product container. 

Ryan O’Dell, chief marketing and sales officer of Safecor Health, LLC, does not mind if the location of his contract packaging facilities are made known. “Serialization is a very manual process as the data elements are much more granular in nature and requires many additional complex steps,” he said. “Making changes and adding new or unique elements like serialization certainly will raise the costs of production in any environment.” The extra, in-line label or package printing costs are not severe. Depending on how fast a packaging line needs to run, and how quickly printers need to serialize, costs for printers can run from $6,000-$20,000.

But serialization goes way beyond printing, and getting the right information to print and ensuring batch records, cGMP processes and other required documentation and regulatory requirements reflect substantial additional costs. 
 

Stephen Barlas is a contributing writer for Contract Pharma. He can be reached at sbarlas@verizon.net.