A draft guidance recently issued by the Food and Drug Administration1 provides specific recommendations for pharmaceutical manufacturers on the use of inks, pigments, flavors, and other molecular taggants used as physical-chemical identifiers (PCIDs) in immediate release film coatings for anticounterfeiting measures. This guidance is significant to the pharmaceutical industry because it provides clarity for the requisite regulatory filing paths when considering the use of PCIDs. It also outlines the requirements for selecting and incorporating a PCID on solid oral dosage forms (SODFs) in new drug applications (NDAs), abbreviated new drug applications (ANDAs), and post-approval changes.
According to the guidance, specific design and location considerations must be met when selecting and incorporating PCIDs. For example, PCIDs must be comprised of approved excipient materials generally recognized as safe (GRAS) or included in the Center for Drug Evaluation and Research’s (CDER) Inactive Ingredient Guide (IIG) of approved substances, or a combination thereof. The preferred method for incorporating PCIDs is through an immediate-release tablet film coating or ink blend that is applied directly to a SODF. The PCIDs are intended to be added as a post-approval change to the tablet coating without any modifications to the existing manufacturing process or product formulation. It is important to note that the guidance does not apply to on-dose authentication techniques that require a manufacturing process change for application. Process changes lead to a more complicated regulatory filing path.
Provided that several critical considerations are met, the guidance lowers the barriers for pharmaceutical manufacturers to begin using PCIDs as an anticounterfeiting strategy because the post-approval incorporation of PCIDs is considered to be an annual reportable (SUPAC Level 1) change. As a result, location considerations of where to place the PCID in the SODF, and the material formulation of the selected PCID, are paramount for drug manufacturers to reduce the regulatory burden. When the selected PCID meets all of the parameters presented in the guidance, no prior approvals are required by the FDA to incorporate them. The guidance does require drug manufacturers include specific data related to the use of PCIDs on-tablet in the company’s next annual report.
Covert Micro-Tag PCID Technology
Perhaps the most significant breakthrough in PCIDs is the development of covert markers, or micro-tags, embedded with unique information for the purpose of authenticating SODFs.
®mark® covert marker technology has been available for several years, but with the passing of the new FDA guidance for PCIDs, the commercial utilization of this technology for on-dose authentication in the pharmaceutical industry is more defined. The On-Dose ID micro-tag technology is made possible through an alliance between Colorcon, Inc., a world leader in the manufacture and development of specialized film coatings and at the forefront of on-dose authentication, and ARmark Authentication Technologies, LLC, developer of custom authentication systems.
Forming an alliance to use ARmark’s micro-tag technology in Colorcon’s tablet coating process was a natural progression for both companies, as each was evaluating ways to broaden the scope of their individual authentication capabilities. ARmark formulated the on-dose covert marker, or micro-tag, from approved GRAS or IIG substances. The company manufactures the micro-tags under cGMP conditions to meet another important requirement outlined by the guidance document. By leveraging the coating expertise of Colorcon, both companies spent significant development time identifying the ideal product construction to be compatible with Colorcon’s existing film coatings and coating processes.
The end result is an on-dose authentication solution with significant benefits to the pharmaceutical industry. The micro-tags are applied directly to pharmaceutical tablets during the film coating process for reliable placement on each and every tablet without changing any aspect of the existing film coating process. Colorcon is the exclusive marketer of the on-tablet micro-tag technology as a new option for anticounterfeiting protection to drug manufacturers.
An Indisputable Fingerprint
There is no other covert authentication solution on the market today that offers the flexibility of composition, the ease of integration into the product, and the simple detection that the ®mark micro-tags deliver. By applying these markers during the tablet coating process, drug manufacturers have indisputable proof to authenticate their solid-dose pharmaceutical products.
The micro-tags function as a unique hidden fingerprint that is embedded with information specified by the brand owner. Compatible with other covert or overt identification technologies, the micro-tags are customized to hold significant amounts of information in a space of 75-110 microns, smaller than the diameter of a human hair. The information included in the micro-tags is customized to each client, and may contain multiple levels of security such as lot and batch ID numbers, country codes, dates, logos and other text, patterns, shapes and symbols. The presence of forensic coded signatures is an added level of security that makes this technology virtually impossible to replicate or reverse engineer.
Micro-tags are embedded with unique information specified by the brand owner in a space smaller than the diameter of a human hair. 50x magnified image shows micro-tags on the surface of a blue film-coated tablet.
The information-laden micro-tags are seamlessly integrated as a PCID without any additional approvals or validation processes. This is accomplished by adding the micro-tags to an immediate release film coating and then applied during the normal tablet coating process of an approved film-coated product. The approach enables pharmaceutical manufacturers to avoid any modification to the production processes as well as any costly capital investments for additional machinery. Incorporating the covert micro-tag PCID via the tablet film coating provides the added assurance that every dose is marked without any negative impact on productivity.
The micro-tags become invisible to the naked eye once they are incorporated into a film coating, however, they are easily identified with ®vision® systems. These are simple, reasonably priced, hand-held optical tools that authenticate a product by magnifying the micro-tags at any stage following the coating process. The simplicity and portability of the ®vision system enables accurate, in-field detection within a matter of seconds without destroying the SODF sample.
®vision systems are a portable and cost-effective
means of authenticating products at any stage within the supply chain.
Another major benefit of this vision system is the interoperability of the ®vision® system. This system does not require sophisticated external databases, communication networks or integration into complicated data systems or laboratory sites to authenticate a product. All that is required is a visual confirmation that the micro-tags are present and contain the correct information by viewing them with one of the ®vision tools.
A major advantage of this anticounterfeiting technology to the pharmaceutical industry is that companies may now utilize the information embedded within the micro-tag to immediately understand a product’s traceability. Because a brand-owner has the ability to specify the information included in the micro-tags, intelligence can be gained beyond the confirmation of product authentication. Not only can the micro-tags prove authenticity of the SODF, but they can also contain information that sheds light on the distribution practices once a product leaves the manufacturing site.
For example, a drug manufacturer may choose to include batch and/or country codes as part of the information included in a micro-tag. At any point within the distribution network, the tablets can be traced and examined with ®vision to validate authenticity, or identify possible sources of counterfeiting. Likewise, any points of illicit diversion can be identified to enable a swift response.
Another example of how the encrypted information contained within the micro-tags provides intelligence can be seen during a product recall. Instances have occurred where manufacturers have received more product back from a recall than what was actually produced, leaving many unanswered questions as to the authenticity of the returned goods. From a track and trace perspective, the micro-tags can provide the technology to distinguish authentic product from adulterated supplies. But when these tags include information such as batch or country codes, the drug manufacturer can take a closer look at understanding where the product originated to gain insight as to how the product was handled in the field.
Inside/Outside Approach to Authenticity
The majority of anticounterfeiting or authentication approaches used today focus on primary packaging and labeling. While any approach offers a level of security, it stops short of authenticating the product inside the package. Even with RFID technology, the possibility exists that a system could be tampered with or that the labeling itself is fake. Combine this with the susceptibility for a breech at the point of product repackaging, and the possibilities for a counterfeit product, or diverted product, to enter the system are compounded.
All of these approaches focus on proving the packaging is authentic, not necessarily the end product. When used in a tablet coating, the ®mark covert micro-tag technology gives drug manufacturers the confidence to mitigate the security concern of repackaging because the product is identifiable, protected and authenticated. The inherent power of the micro-tag technology is that it can also be formulated directly into or on the product packaging. So, with on-dose application and integrated packaging use of this technology, the brand owner has proof positive that what is in the packaging is an authentic product. Similar to how the micro-tags are loaded into the film coating mixture for application onto an individual tablet, micro-tags can be formulated and loaded into the materials used for drug blister packs, plastic labels or films. By applying micro-tags to RFID labels, manufacturers can be assured that they are applying unadulterated labels for track and trace.
®mark® On-Dose ID authentication technology is “interoperable” meaning that it is not shackled to any complex electronic infrastructure requiring sophisticated data management for detection capability. Whereas most covert technologies are rendered novel by the reader technology, ®mark micro-tags are indisputably different because the science is in the marker itself. The micro-tags are seamlessly integrated into existing tablet film coating manufacturing processes without any additional capital expense or system downtimes. These features, and the broad range of available compliant materials for constructing PCID technologies, provide brand owners universal flexibility for protection, and the confidence that this micro-tag authentication technology is 100 percent reliable.
About the Authors
John D’Ottavio, Quality and Regulatory Affairs Manager, ARmark Authentication Technologies, LLC
John D’Ottavio is currently the Quality and Regulatory Affairs Manager at ARmark Authentication Technologies. He is responsible for all aspects of quality management as well as working with clients in the medical and pharmaceutical communities to integrate authentication technologies for brand protection. He holds a B.S. in Chemical Engineering with honors from Bucknell University as well as a M.S. in Management of Technology, an executive program at the University of Pennsylvania that is jointly sponsored by Penn Engineering and The Wharton School of Business. He has 14 years of industry experience and began his career in project engineering and compliance engineering. Mr. Dottavio joined Adhesives Research Inc., the parent company of ARmark Authentication Technologies , LLC, in 1998 and served in leadership roles related to custom polymer synthesis, product development and operations management. He has held roles of increasing responsibility related to commercial development including the identification of new market segments and applications that would benefit from the company’s products and technologies.
John can be contacted at:
ARmark Authentication Technologies, LLC, 400 Seaks Run Road, Glen Rock, PA 17327
Email: [email protected], Phone: (717) 227-5932
Business Development Manager, Colorcon
MaryAnn Hegedus is currently the Business Development Manger for Brand Enhancement Services at Colorcon where she works with pharmaceutical and biotech companies to establish the market image for new pharmaceutical products and collaborates with them to implement on-dosage authentication strategies.
Ms. Hegedus began her career in medical research and clinical laboratories after graduating from Bucknell University and pursuing graduate studies at the University of Pittsburgh School of Medicine. She has over 20 years of sales, marketing, and communications experience in the healthcare and biotechnology areas. This experience enables her to understand the underlying issues in the healthcare and pharmaceutical industries, and has provided her with negotiating, leadership and motivational skills, as well as a vast network of businesses and associations. Ms. Hegedus has worked extensively in both public and private sectors. This experience has given her the vision to create and implement successful action plans for project development. In her senior-level sales and marketing positions she has been responsible for the image development and marketing of healthcare organizations, as well as for regulatory compliance and employee education on regulatory issues. She has served as a consultant to several high-tech companies where she developed strategic plans for communications, business development, and project development. Her work has involved regional collaborations of public and private sectors in the areas of economic development, workforce development, and education in the pharmaceutical and biotech fields.
MaryAnn can be contacted at:
Colorcon, Inc., 415 Moyer Blvd. , West Point, PA 19486-0024
E-mail: [email protected], Phone: (215) 699 -7733
®mark®, and ®vision® are registered trademarks of ARmark Authentication Technologies, LLC.
ARmark® and ARvision® are registered trademarks of Adhesives Research, Inc.