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Representatives from Pfizer R&D, DEM Solutions, Colorcon, and ARmark Authentication Technologies provide insight into recent tablet-coating technologies.
See a video demonstration at the end of this article
Maximizing physical-chemical identifiers: Colorcon and ARmark's visual and covert film-coating technologies
The regulatory landscape for improving anticounterfeiting technologies has greatly improved in recent years, especially with regard to solid-dosage coatings. According to John D'Ottavio, quality and regulatory affairs manager for ARmark Authentication Technologies, LLC, FDA's 2009 draft guidance on physical–chemical identifiers (PCIDs), Incorporation of Physical-Chemical Identifiers into Solid Oral Dosage Form Drug Products for Anticounterfeiting, opened the door to new security options for the pharmaceutical industry.
"The majority of anticounterfeiting or authentication approaches used today focus on primary packaging and labeling, and not the product itself," he says. "But the guidance offers specific recommendations regarding the use of inks, pigments, flavors, and other molecular taggants in immediate-release film coatings on solid oral-dosage forms."
PCIDs offer several benefits to industry. "In the fight against counterfeiting, one of the more interesting breakthroughs in PCID technology can be seen in the development of (R)mark On-Dose ID microtags, a technology created by ARmark Authentication Technologies, LLC and Colorcon, Inc. By leveraging the tablet coating expertise of Colorcon, a world leader in the manufacture and development of specialized film coatings, and ARmark's customized microtag authentication technology, the two companies collaborated to enable greater security by authenticating solid oral dose pharmaceuticals.
The microtags are embedded with unique information for the purpose of authenticating solid oral-dosage forms, explains D'Ottavio. "The microtags 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 of an approved product. This flexibility can save ample costs in terms of additional machinery."
Adds Kamlesh Oza, film-coating general manager at Colorcon, the covert microtags are custom-developed from approved excipient materials listed in FDA's Inactive Ingredient Database (IID). "Their unique physical–chemical characteristic make it possible to authenticate legitimate dosage forms and identify counterfeits under magnification. These markers are invisible to the naked eye," says Oza.
The microtags function as a unique hidden fingerprint embedded with information specified by the brand owner, explains D'Ottavio. The tags are compatible with other covert or overt identification technologies, and are made to hold significant amounts of information in a space of 75 to 120 µg (i.e., smaller than the diameter of a human hair). "The information included in the microtags is customized to each client and may contain multiple levels of security, such as lot and batch ID numbers, country codes, dates, and logos as well as other text, patterns, shapes, and symbols. These types of forensic-coded signatures offer an additional level of security that makes the technology virtually impossible to replicate," says D'Ottavio.
ARmark's trademarked (R)vision systems allow for easy identification of the microtags. Simple hand-held optical tools authenticate a product by magnifying the microtags at any stage following the coating process. "The simplicity and portability of the (R)vision system enables accurate, in-field detection within a matter of seconds without destroying the drug sample," says D'Ottavio. "Another major benefit of this system is its interoperability. For example, the 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 microtags are present and contain the correct information."
Pearlescent coatings. According to Colorcon's Oza, the pearlescent pigments in fully-formulated film coatings are also considered PCIDs under the 2009 FDA draft guidance. Pearlescent coatings, in general, could increase counterfeiting protection because the unique color-shifts across the tablet surface are difficult to duplicate without knowing the specific combination of pigment properties and processing procedures.
Explains Oza, "A multitude of colors can be achieved using the same chemical entity controlled by various parameters that are difficult to reverse-engineer. Pearlescent coatings are also easily recognized by physicians, pharmacists, and patients as the original manufacturer's product. In this sense, visual identification can be further enhanced by using unique colors, coupled with a tablet's shape and size, or by using printing methods to place unique images and logos on the tablet's surface."
In terms of regulatory implications, Oza says that the pigments contained in the pearlescent coatings meet current 21 CFR colorant regulations. The coatings are custom-developed from approved GRAS ingredients or listed in FDA's IID; produced under cGMP conditions; compatible with existing coating processes; and typically have no impact on dissolution or stability.
He adds that, "the addition of the microtags or pearlescent pigments to an existing immediate-release film coating would typically be considered a SUPAC Level 1 Change and documented in a company's next annual report. This flexibility can allow for quick incorporation of this technology into drugs which are known or suspected counterfeit targets."
Figure 1 (ARmark): Microtags, with unique information specified by the brand owner, can be embedded in a space on a tablet smaller than the diameter of a human hair. Magnified image shows microtags on the surface of a blue film-coated tablet.
Supply chain. Covert on-dose microtag technology is also important for addressing growing supply-chain concerns throughout industry because it enables companies to use the information embedded within the microtag to immediately understand a product's traceability. "Not only can the microtags prove authenticity of the solid oral-dosage form, but they can also contain information that sheds light on the distribution practices once a product leaves the manufacturing site," explains ARmark's D'Ottavio.
"From a track-and-trace perspective, the microtags can provide the technology to distinguish authentic product from adulterated supplies," he says. "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."
Looking ahead, Colorcon's Oza comments on what the future of drug-anticounterfeiting technology may hold. "Due to the complexity of today's distribution system, no single anticounterfeiting technology can guarantee full counterfeit protection. However, if a drug product is designed with layers of identification on the dosage itself, and then packaged with a variety of features that are hard to duplicate, counterfeiters may turn their sights elsewhere," he says. "The key is to ensure that a pharmaceutical is made difficult to duplicate. Procuring noncommodity coating options will impart the most security."
Accelerating tablet shape selection: Pfizer and DEM Solutions' predictive computational model
The following section is provided by William R. Ketterhagen, senior scientist, and Mary T. am Ende, associate research fellow, both with Pfizer Worldwide Research & Development, and by Richard D. LaRoche, vice-president of engineering and US general manager, and Oleh Baran, senior consulting engineer, both with DEM Solutions. The authors discuss a recently developed predictive computational model that can help guide pharmaceutical manufacturers in the selection of tablet shape and operating parameters for a given equipment geometry to ensure film-coating uniformity.
Designing and developing robust drug products can be a costly endeavor, especially when commercial-scale studies must be performed to determine nonscalable or unpredictable process parameters. Even in tablet-film coating, where some aspects, such as the thermodynamic conditions in the pan and spray atomization are relatively well understood, coating uniformity can vary for tablets of different core shapes and different coating-process conditions (1, 2). In this regard, the coating process is not entirely scalable from laboratory studies due to differences in tablet-mixing in the pan (3). The introduction of a new tablet shape, for example, can result in unexpected variations in the uniformity of film-coating thickness, requiring physical testing that is costly in time, materials, and labor.
Although some experimental work can be avoided through the use of models, poor coating uniformity often requires experimental trials to determine the operating conditions that produce desired coating results when moving from laboratory to commercial scale (1, 2). As a solution, Pfizer Reseach and Development has developed a predictive computational model using EDEM, discrete element method (DEM) software developed by DEM Solutions. The method has been confirmed experimentally to guide selection of the tablet shape and operating parameters for a given equipment geometry such that uniform film-coating thickness is obtained (4).
Uniformity of film-coating thickness is an important tablet quality attribute for a number of reasons. Poor uniformity or significant variability in film-coating thickness, can lead to a range of issues, depending on the purpose of the coating. In the case of coatings containing an active pharmaceutical ingredient (API), variability in potency between tablets arises directly from coating variability. For a functional coating governing the drug-release profile, variability in thickness can lead to variable drug-release profiles. Finally, high levels of variability for cosmetic coatings results in longer process times to ensure that all tablets have received a sufficient amount of coating.
In practice, obtaining uniform coating depends on good mixing of the tablets in the coating pan and a uniform distribution of tablet orientations in the spray zone to ensure uniform exposure of all sides of each tablet to the coating spray. The tablet-flow dynamics are governed by several factors, including the equipment geometry, the presence of any mixing elements (e.g., baffles), the conditions under which the equipment is operated, and the properties of the tablet cores, including size and shape. To fully explore the effects of each of these factors on film-coating uniformity necessitates a large number of physical experiments. Developing a model to study these effects in silico offers great savings in time, material, and labor costs.
DEM models are capable of accurately reproducing particle behavior in a number of pharmaceutical manufacturing processes and are growing in use throughout the industry (5). During the past few years, Pfizer has developed DEM models of various processes involving solid dosage forms using EDEM, a commercial DEM software package. Previous reports in the literature on film coating uniformity are limited to spherical, standard round convex (SRC), or oval tablet shapes, and are often focused on operating conditions rather than tablet shape (6–8). The computational approach reported here predicts both intertablet (i.e., uniformity between tablets) and intratablet (i.e., uniformity between surfaces of a given tablet) coating uniformity and allows for the study of many tablet shapes, including less common almond or bullet tablet shapes, permitting rapid screening of tablet shapes and operating conditions that ensure quality of tablet coating uniformity.
To investigate intertablet coating uniformity, EDEM simulations of the operation of pan coaters were carried out at various batch sizes, pan speeds, and different tablet shapes. The results were analyzed to determine the distributions of the residence time per pass through the spray zone for each tablet and the circulation time between successive appearances in the spray zone (see Figure 2). For conditions in which these distributions are wide, poor intertablet coating uniformity usually results. In a laboratory-scale coating pan, simulations predicted that the residence-time and circulation time variability both decrease with faster pan speeds. The effect of pan loading is mixed—residence time variability decreases with increasing loads but circulation time variability increases with increasing loads. The net effect in this case is an increase in variability for larger pan loads. Thus, improved intertablet coating uniformity is expected for faster pan speeds and smaller batch sizes, but consideration must also be given to maintaining reasonable process throughput, and the potential for increased tablet attrition that may occur at fast pan speeds.
Figure 2 (PfizerâDEM): Simulation image of bullet shaped tablets in a laboratory-scale film coating pan where intertablet coating variability is shown by varying degrees of blue color on each tablet, indicating the total residence time in the spray zone for a given tablet.
Tablet shape was found to have little effect on intertablet coating uniformity but did, however, play a role in intratablet coating uniformity due to the extent to which tablets have a preferred orientation as they pass through the spray zone. The analysis of several different tablet shapes shows a trend with an orientation index (OI)—a quantitative measure of the existence of a preferred tablet orientation in the spray zone—that correlates with a mean aspect ratio of the tablet shape (see Figure 3). Tablets with a smaller mean aspect ratio tend to have improved intratablet coating uniformity over those with a larger mean aspect ratio.
Figure 3 (PfizerâDEM): The Orientation Index (OI) describing the extent of a preferred orientation in the spray zone- and the resulting likelihood for poor intra-tablet coating uniformity-is shown for several tablet shapes. The mean tablet aspect ratio (A) is defined by the tablet length (L), width (W), and thickness (T). The dashed line represents the least squares linear fit to the data.
The deployment of EDEM modeling in Pfizer drug-product development has accelerated the decision-making process by predicting, before process scale-up, the performance of commercial tablet shapes at process scale. The modeling is rapid, broadly applied across the solid-drug product portfolio, and has flexibility to assess unique shape decisions early in the development process.
The value of this predictive computational tool was estimated using DoOptima software (Decision Options, LLC), which uses a market normalization process to analyze the impact on projects at various phases accounting for the typical number of projects transferring to commercial scale per year, the material, manufacturing, supplies, and labor costs associated with conducting the trial compared with the cost of the software license and resources for the simulations. The net present value of predictive modeling for film-coating scale-up was estimated at approximately $500,000 in the first year (9). Based on this success, the future focus should be to continue to advance and deploy predictive computational models to support drug product development and commercialization.
See a video demonstration from DEM Solutions here.
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2. A. Aliseda et al., Int. J. Multiphas. Flow 34, 161–175 (2008).
3. S. Garcia-Munoz and D. Gierer, D., Int. J. Pharmaceutic. 395, 104–113 (2010).
4. W.R. Ketterhagen, Int. Jrnl. Pharmaceutic., In press (2011).
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8. J.D. Perez-Ramos et al., AAPS PharmSciTech6, E127–E136 (2005).
9. M.T. am Ende, B.C. Hancock and K. Huta, "An Approach for Estimating the Value of Computational Tools in Drug Product Development," presented at the AIChE Annual National Meeting, (Salt Lake City, UT, Nov. 10, 2010).