Tracking, security and traceability are driving pharmaceutical packaging as they never have before. New packaging machinery and coding technologies promise to improve patient safety, as well as the way that drug companies manage their supply chains.
In June, the U.S. Food and Drug Administration (FDA) proposed a rule that would mandate barcoding, at the unit-dose, for pharmaceuticals dispensed at hospitals and nursing facilities. The following month, the Agency rolled out a new initiative intended to examine technologies that could help secure U.S. pharmaceuticals against a rising tide of counterfeits.
Both moves have important implications for the future of pharmaceutical packaging. Not only is the packaging process becoming far more complex, with increasingly sophisticated IT and control systems, packagers are adapting to stringent oversight by FDA "We've gone from being tin knockers to paper pushers," says Linc Jepson, an executive vice president of equipment supplier and systems integrator NJM/CLI Packaging Systems International in Lebanon, N.H.
"There are many complexities to how pharmaceutical products are packaged, what the packaging media are, and what distribution channels are used, especially in the U.S.," comments Andrew Gill, an analyst with PA Group (Cambridge, U.K.), an industry consultancy. "Nevertheless, the overall direction is clear: the industry is moving toward a structure where there is an identifying code on products, so that they can be tracked from point of manufacture to point of use."
While demand for packaging equipment continues to show healthy growth (Figure 1), the market for pharmaceutical packaging, particularly such unit-dose products as blister packs, is moving at several times the rate of inflation. Unit dose packaging, which includes the blister packs and foil strips typically seen in physicians' sample kits, has long been promoted by equipment vendors in Europe, where most ethical pharmaceuticals are distributed that way.
Blister packs and foil strips offer longer shelf life, due to use of barrier materials that prevent moisture migration, they make it easy to spot tampering, and also manage to meet the twin challenges of being "child resistant" and "senior friendly"--both of which are mandated by the federal Consumer Products Safety Commission (CPSC).
However, unit-dose packaging entails higher equipment and media costs. Since each package is formed, filled and sealed at one station on a packaging line, the operations are more complex than for traditional packaging. "Blister packaging machines" require more precise control, and more work on setting up and validating process parameters," says Howard Leary, vice president of engineering at systems integrator Luciano Packaging Technologies (Somerville, N.J.). "They need specified pressures, temperatures and dwell times for applying and sealing the foil backing. It's more sophisticated machinery that requires a higher level of expertise to operate and validate."
In addition, the whole concept of unit packaging runs against longstanding tradition. Hospitals and large drugstore chains may like its efficiency and traceability, but pharmacists look askance at a system that cuts them out of the distribution process.
Like equipment for blister packs and foil strips, blow-fill-seal (BFS) machines, used for parenteral (liquid-injectable) pharmaceutical products, are only slowly making headway in the U.S. against traditional vial and ampule packaging techniques. With BFS machines, a container or "parison" is blow-molded from a variety of plastics in one section of the machine, then filled with the parenteral product in a next section, and finally sealed, a step that involved closing or cutting off the head of the parison, and attaching some type of cap or cover. The entire process is performed within an isolation chamber and both the parenteral product and process air are filtered to aseptic levels of cleanliness.
One significant advantage of BFS technology is that product codes, lot numbers or other identifiers can be engraved right on the package by using etched molds or pin sets that touch the wall of the parison as it is being molded. "Overall, this makes for a container that is inherently tamper-resistant, and doesn't need labeling to be applied," notes Chuck Reed, sales manager at Weiler Engineering Co. (Elgin, Ill.). Although widely used in Europe and the rest of the world, BFS technology still has made only limited progress in the U.S., notably for respiratory treatments and ophthalmic solutions, he says.
Raising the Bar on Barcodes
Now that unit-dose packaging is starting to gain ground in the U.S., the question is: What type of coding will go on those packages? The FDA's plan to mandate barcoding on most prescription medications followed a year of near-consensus debate, with proponents claiming that unit-dose barcoding would drastically reduce medication errors in healthcare settings. FDA doesn't currently mandate barcoding, but it does expect that hospitals will begin to prefer barcoded unit-dose packages.
The proposed rule would not be enforced before late 2006, so no one expects an immediate wholesale conversion to unit dose packaging. But, as Peter Mayberry, executive director of the Healthcare Compliance Packaging Council (HCPC, Falls Church, Va.), points out, the billions of dollars in expected savings from reduced medication errors will be a strong inducement for hospitals to embrace barcoding. The Council, which exists to promote unit-dose packaging, has advocated barcoding at that level. In addition, the Council has asked the CPSC to clarify its rules on child-resistant design features so that the benefits of unit dose packaging would become more apparent; CPSC announced in August that it would formally study the Council's petition.
The pharmaceutical packaging industry is likely to adjust smoothly to this barcoded future---even if medications being routed to hospitals continue to be repackaged in unit dose form while other distribution channels remain the same. But many of the major pharmaceutical manufacturers aren't waiting for a final FDA rule. In May, Abbott Laboratories, Abbott Park, Ill., completed its conversion to 100% barcoding of all of the Hospital Products Division output, primarily injectable medications or intravenous solutions. The changeover involved more than a thousand types of packaged products, and represented a "strategic investment" on the part of the company, according to a spokesperson. Abbott's Pharmaceutical Products Division, which handles most of the pill-form products, is also marching toward that goal; the Division's bottled products already are mostly barcoded, and testing is under way for remaining products.
Part of the challenge that pharmaceutical manufacturers have had is developing barcoding small enough to fit on unit-dose packaging. Abbott worked with the Uniform Code Council, the national body governing bar code standards, to make use of the Reduced Space Symbology (RSS) protocol for creating these codes. Pfizer, GlaxoSmithKline and Baxter Healthcare also are expanding their use of the technology, according to industry sources.
Barcode equipment manufacturers are responding to marketplace demands with products and information-systems integration services. Zebra Technologies (Vernon Hills, Ill.), for example, has joined up with Prisym, Inc. (Charlotte, N.C., and a subsidiary of U.K.-based Map80 Systems Ltd.) to integrate Zebra's barcode printing systems with Prisym's label-generating software. Both companies aim to meet FDA 21 CFR Part 11 requirements' evolving rules for electronic recordkeeping and verification.
Up the Validation Learning Curve
Mention 21 CFR Part 11, along with FDA's other validation and recordkeeping requirements, and most packaging systems suppliers and integrators roll their eyes.
"The pharmaceutical industry and its packaging suppliers have had a lot to learn from each other over the past five years," says Luciano's Howard Leary. "The whole process of qualifying and validating packaging equipment has become much better understood. Suppliers now know that they have to provide detailed design documents with their equipment. Site acceptance testing is much more rigorous as well."
The packager Eon Laboratories, Inc. in Laurelton, N.Y., found out last February exactly what can go wrong, when FDA inspectors cited the company for eight violations of manufacturing practices. At issue were the company's labeling machines, the way that inventory was sorted and stored, and the way that packaging equipment was maintained. Mislabeling had resulted in 100-unit bottles of Nabumetone 500 mg being labeled as 750mg tablets. The lots were recalled.
By this May, the company reported that it passed muster in a follow-up FDA inspection. Eon wouldn't elaborate on how it revamped its packaging lines, but a spokesperson said "we put a lot of resources against resolving these problems, and everything turned out well."
To prevent this type of worst-case scenario, some pharmaceutical manufacturers assume that the wisest course is simply to validate, and bring under 21 CFR Part 11 management everything along their packaging lines. This isn't always necessary, experts say.
"The most recent guidance on doing risk-based analysis of electronic recordkeeping issues means, in part, that there is no standard way to approach these tasks," says Nancy St. Laurent, president of STL-Lincs, an Omaha, Neb.-based packaging consultant. "For example, you might assume that it's necessary to keep track of relative humidity for products stored in a warehouse. But for a manufacturer operating in an arid region of California, where humidity is low year-round, risk analysis tells you that this could be a non-issue."
St. Laurent, who is also co-chair of a committee developing a "Baseline Guide" for packaging systems under the aegis of the International Society of Pharmaceutical Engineers (ISPE), emphasizes that manufacturers dealing with validation and documentation issues must bring validation experts into the design process as early as possible.
Another approach to dealing with the "21 CFR black hole," as Rick Pierro, president of systems integrator Superior Controls (Plaistow, N.H.), puts it, is simply to ensure that recordkeeping is not done electronically. "I have one pharmaceutical customer who specified paper-based, circular-chart recorders for his packaging line, rather than a digital data acquisition system, simply to avoid 21 CFR altogether [in part of a packaging line]."
Other integrators and equipment vendors agree, noting that the critical aspect of 21 CFR Part 11 involves software or control systems that can be adjusted or modified, requiring tracking of who made the adjustments and when. Some packaging machinery can simply be hardcoded. Since there is no ready access to the control software, there is no need for this type of tracking.
The Next-Generation Packaging Machine
Nevertheless, the clear trend is toward a unified system for both controlling production processes and storing validated data. The market research firm ARC Advisory Group (Dedham, Mass.), sees a move to "Generation 3" packaging machinery, combining a distributed network of intelligent drives on packaging machines with a "network-centric" architecture of centralized control and data storage. In essence, there would be one central station that could look out on an entire packaging line, but each subsystem of the line would have sufficient control intelligence to manage itself.
Superior Control's Pierro says that his company has installed several such systems. Their style of network-centric supervisory control is to have an intranet, running on Ethernet connections, that communicates to a central server. That computer's data storage system is backed up with RAID (random array of independent drives) data storage, which provides both rapid data acquisition and automatic backup. With RAID technology, the backup is "hot," meaning that if one hard drive broke down, others could immediately pick up the slack.
"Using Internet protocols, another feature of Ethernet/server systems, you can easily adapt to wireless communications within the plant," Pierro says. The wireless networks have data transmission rates of 11 to 54 Mbps (faster than most hardwired Ethernets), which allays some worries about communication breakdowns. However, the communication of actual control instructions can still occur via hard wire; the wireless system is more geared toward data acquisition, and when a breakdown occurs, the system can re-send repeatedly until a message is completed.
Similar digital evolution is occurring on the hardware side of packaging machinery "the actual grippers, pill counters, bottle cappers, label applicators and other common machines. Over the past decade, many equipment vendors have evolved from motorized drives to electronic servos, which offer more precise control, faster acceleration and deceleration and a smaller footprint, according to NJM/CLI's Jepson. And, just as barcoding equipment is becoming a more-common add-on to the packaging line, so is machine vision to validate the labeling that occurs.
"High-speed, 24x7 production lines with hot-stamped labels might need multiple vision systems to ensure that the right label is in place on each bottle passing through the machine, and also to inspect the printing so that characters and numbers have not been dropped," Jepson explains. "You might need multiple cameras with complex packaging, such as multi-color, or where the geometry of the package curves the label," he says.
As FDA and the packaging machinery industry come to grips with universal barcoding, radio-frequency identification, or RFID, is looming on the horizon (See Sidebar, p. TK). So far, the technology has been applied in a packaging context only to certain types of products, and not usually at the unit level.
On the other hand, RFID chips are readily available, as are the receivers and related gear. Even some barcode companies, notably Zebra Technologies, are readying RFID solutions for inventory and distribution applications. But it remains to be seen whether the pharmaceutical industry can establish RFID use through its distribution channels, just at the time when barcoding now appears to be universally accepted.
"This has the potential to drive the industry crazy," notes Frank Bieganousky, a consultant with Montesino Associates (Wilmington, Del.). "It has taken a long time to establish bar coding, and now this appears." However, liability concerns for manufacturers may propel the issue forward, he says.
It could be considered the Cadillac of RFID and sensor technology, as applied to pharmacetical packaging. A small engineering company in Ottawa, Information Mediary Corp., is in the process of commercializing what it calls the Med-ic Electronic Compliance Monitor (ECM) system for high-value, complex medications (or combinations of medications) in which the prescribed regimen of dosages can be monitored by patients themselves.
As explained by Michael Petersen, company co-founder, ECM originated with a desire to provide medications in a package where, for example, the patient could be reminded by an alarm to take the next dosage. However, with the upwelling of interest in anti-counterfeiting and tamper resistance, the ECM might find its niche as a solution for that problem as well. "Barcodes and other anti-tampering measure will not cut it any more, because they've become too easy to forge," he says. One of the advantages of RFID technology is that it can be encrypted for virtually total control of tampering.
Information Mediary's ECM system comprises a unit-dose packaging system, a sensor grid that is printed on the inner surface of the foil backing, and an RFID chip that provides product codes, lot numbers, and medication instructions. Shorewood Packaging (a business unit of International Paper) is partnering with Information Mediary on the development, and this company is also looking to support from others in the business, such as Flint Ink Corp. (Ann Arbor, MI), to provide electrically conductive inks to print the sensor grids.
With the right RFID chips, audible instructions could be given for taking medications. Specialized sensors could monitor the temperature and shelf life of the medication. The sensor grid provides a ready-made way to indicate product tampering; when a line on the grid is broken, it is evidence that that dosage has been opened.
All this is not cheap: Petersen says that the system could run as high as $12 per package, but that could fall to around $5 as production volumes ramp up. The company is about to begin a clinical test with HIV medications, and has already produced 250,000 of the RFID tags. "This technology represents a different level of patient interaction," he concludes.