May 29, 2018 PAP-Q2-18-FA-003
By the time a drug reaches the fill-finish stage, it has been through upstream processing, cell culture or fermentation and downstream purification.1 Perhaps the hesitation in experimentation with fill-finish stems from the fact that the product is of extremely high value at this particular phase of operations. In this form, it is the result of all the manufacturing processes thus far. In addition to the labor that has gone into these vials, the fill-finish step is crucial from a compliance standpoint.
Errors that occur during fill finish could lead to contamination, formulation issues or dosing problems, which could mean not only the loss of product but detrimental health risks and/or production failure.1
The many challenges associated with fill-finish operations have largely led to its outsourcing. According to the 12th Annual Report and Survey of Biopharmaceutical Manufacturing, an industry wide survey conducted by BioPlan Associates, seven out of ten respondents reported some outsourcing of fill-finish.2 Fill-finish operations were outsourced most frequently, with respondents relying on external organizations for over one third (34.5%) of their fill-finish needs.2
Results from this survey also indicated the tremendous interest in developing these operations further, and the pressure that CDMOs are facing to evolve operations, and thus meet the demand for a more advanced process. According to the survey, out of ten respondents, eight said they were planning to add a minimum of one new technology to their fill-finish operations within the next two years. Of these respondents, the majority were employed by contract manufacturing organizations.2
The widespread demand to improve packaging is perhaps best exemplified through the race to meet the FDA’s upcoming deadline for a fully traceable supply chain, following the passage of Drug Supply Chain & Security Act (DSCSA). The act mandates the use of an electronic track and trace system to identify prescription drugs throughout the United States.3
Going forward, serialization must be built into operations — and it can be argued, for good reason. According to the FDA, the DSCSA will “enhance the FDA’s ability to help protect consumers from exposure to drugs that may be counterfeit, stolen, contaminated or otherwise harmful. The system will also improve detection and removal of potentially dangerous drugs from the drug supply chain to protect U.S. consumers.” At the 25th Annual Life Sciences and Technology Conference presented by the International Society for Pharmaceutical Engineering–Carolina-South Atlantic Chapter, keynote speaker Paul McKenzie, Ph.D. and Executive Vice President for Biogen addressed this pressing issue. “Eighty percent of product recalls from the market are due to packaging errors,” he noted.4
Though serialization has the potential to drastically change the entire supply chain, with the patient ultimately benefiting the most, it is not without its challenges. There is a substantial cost burden for the industry to abide by the regulatory requirements of serialization. According to Medicines for Europe, the nonprofit association representing the industry, it will cost the average company €5 million to update packaging and production lines, plus an additional annual running and maintenance fee of €2 million.5 It will cost the pharma industry €5 billion in general, with an implementation and running cost of €90 million annually.5
Aside from the obvious issues involved in financing a serialization production line, additional concerns include serialization overlap, as there is no standard code set up by regulatory agencies.4,5 The lack of regulatory guidelines is another potential issue, as companies have been tasked to serialize operations with very little direction as to exactly how this is to be done. This has led to inconsistencies in what should be serialized. Although entire manufacturing operations should be integrated into serialization, organizations have treated the idea of serialization as limited to packaging. Transparency in the entire supply chain goes beyond packaging, however, and integration is key.
As Olsen pointed out at the annual event, corporate integration is crucial for an organization to successfully and holistically serialize. “Twenty to 25 percent of operational costs is simple product packaging,” commented Olsen. “The OEE (overall equipment effectiveness) in the pharmaceutical industry runs between 40-60 percent. The addition of serialization can reduce efficiency by as much as 5%. This can be a financial game changer for the manufacturer, even big pharma,” he continued.4 There is a fear that this added cost will force smaller companies to abandon operations.
The challenges of serialization extend throughout the supply chain. For companies to take on a new packaging process, new software will also need to be implemented and integrated into operations. Packaging lines must be tested and setup before running.6 Considering the sheer numbers of products being serialized, an increase in the amount of SKUs (or Stock Keeping Units) generated is to be expected and planned for.4 Additionally, these SKUs must be managed. Employee training is necessary to oversee these operations and in efforts to minimize any chance of error. With serialization implementation, compliance trickles all the way down from batch scale to an individual shipping unit.4
Another issue to consider is barcode appearance, which again, has not been strictly delineated by FDA. Without an effective verification process, the barcode does not serve its purpose. A QR code must convey data about the product’s authenticity that translates through the product’s code.7 How this should look and is open for interpretation, though several features must be taken into account, including if the code is readable under a host of conditions and even how the barcode is read and what it means.7 Barcode reading, known as scanning and barcode grading, is another way of saying the code is verified. Barcode grading includes either a number or letter score, which acts to quantify multiple barcodes against each other using known standards as a frame of reference.7
The 2D data matrix barcode is standardized by the GS1 DataMatrix, which is recognized by the International Organization for Standardization and the International Electrotechnical Commission (ISO/IEC). The GS1 standards body works in conjunction with regulators and the industry to develop a set of norms for codifying the serialization information necessary.7 Various organizations including ISO/IEC and ANS have worked out grading standards. These organizations have developed standards of clarity that reflect different attributes of the system. For instance, GS1 DataMatrix barcode features are ranked numerically (4-0 - ISO) or using an alpha system, which is the (A, B, C, D, F) American National Standards Institute (ANSI) scale.7
Attributes considered include decodability, contrast, modulation, fixed pattern damage, grid non-uniformity, axial non-uniformity and unused error correction.7 Decoding of the bar code signifies if it is readable. The bar code’s contrast, or the difference between the colors that comprise the code, such as a white background with black squares or dots, is also taken into consideration. This extends to modulation, which includes the differences in color contrast throughout the bar code, with less being better. Fixed pattern damage is another attribute; the quality of squares or dots that make up the barcode’s perimeter as well as the surrounding negative space of the barcode. Grid non-uniformity is how the bar code is able to fit in a specific boundary, and axial non-uniformity is the alignment of the bar code within its horizontal and vertical parameters. The unused error correction is the amount of error correction that is in a symbol. It corrects data that is lost due to an issue, such as damage or poor printing.7 Under best circumstances, the barcode is graded in its ultimate form, for instance on a label that is in a bottle or case. How a bar code is printed will also obviously affect the way it looks, with three primary types of printing currently in use. These include thermal transfer, inkjet and laser ablation/marking.
As the industry moves towards the adoption of QR codes, which are essentially data matrixes in the supply chain, security of supply is ultimately more assured. There is little doubt that as the industry meets the demands of the FDA, standards of barcodes will become more sophisticated, with new methods for production and printing achieved, as well as more information conveyed, and easier. This will lead to, as the national regulating body has demanded, a decrease in the counterfeited prescription drugs distributed in the United States and eventually, around the world.
Packaging is not without its challenges. The last step in getting a drug to market is also the riskiest, and the site where the most information is at risk of being lost in translation from the manufacturer to the patient. Innovations in packaging will continue to build, especially with the FDA mandate months away from testing the entire industry. However, the response will no doubt be positive sum, as transparency and safety are ensured throughout the supply chain. What’s perhaps most interesting will be how the industry interprets this mandate — especially considering holograms and chips are all possible responses to the open call to end counterfeiting.8
Dr. Challener is an established industry editor and technical writing expert in the areas of chemistry and pharmaceuticals. She writes for various corporations and associations, as well as marketing agencies and research organizations, including That’s Nice and Nice Insight.