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Sophisticated excipient development, especially for coatings, is staying on top of new challenges and meeting expanding industry needs.
In 1985, when Hubertus Folttmann, now head of global marketing excipients at BASF (Limbergerhof, Germany) started his career in the pharmaceutical industry, his company manufactured a drug product in three strengths, including an 80-mg tablet and a 120-mg tablet. To manufacture the 80-mg tablet, formulators simply replaced 40 mg of active ingredient in the 120 mg tablet with filler. "At that time, the world of pharma was okay," he says, "Health costs were not a topic, and manufacturing costs in the pharmaceutical industry were of minor importance."
(ALEX CAO, RAY MASSEY/GETTY IMAGES. ILLUSTRATION: M.MCEVOY)
Today, concerns about manufacturing costs and process times are at the forefront of fiscal budgets, and improving formulations is on every company's agenda. "Nowadays, smaller tablets are the advantage, and if you need less active ingredient, you are happy because then you need less excipients to formulate it." Not only do patients want to swallow smaller tablets, but if the capacity of process equipment determines the batch size, then there are more smaller tablets in a batch, which means less batch documentation, smaller packaging, less volume for transportation, and so forth. "Nowadays, these issues count," says Folttmann. "Excipients that perform their functions at lower concentration so that less material needs to be handled have a good chance of success in the marketplace."
Functionality and QbD
The US Food and Drug Administration's quality-by-design (QbD) initiative has changed the way excipient suppliers develop, characterize, and manufacture their materials. "We have seen some benefits of implementing QbD into the pharmaceutical manufacturing process, including a reduction in approval delays, a more streamlined approval process and an easier course for implementing postapproval changes," says Nandu Deorkar, director of research and development, laboratory and pharmaceutical products at Mallinckrodt Baker (Phillipsburg, NJ). "However, the concept of QbD can present implementation opportunities and challenges to both raw-material (excipient) suppliers and pharmaceutical manufacturers. As a part of the QbD system, raw-material characteristics and their variability on the process and product quality or performance should be studied and documented. As such, raw materials must be well-characterized and developed using QbD principles to reduce variability"
QbD principles also can facilitate the evaluation of excipient functionality performance and its correlation with physical and chemical properties. Better understanding of excipient properties related to intended uses can help design better dosage forms. "That is where we are getting involved now," says Dave Schoneker, director of global regulatory affairs at Colorcon (West Point, PA), "to build quality into the design from the beginning in terms of what customers want to achieve to make it a better product in the marketplace. In the past there has been a limited number of people within some pharmaceutical companies who could to do that." The company has built a computer-aided design program to help pharmaceutical clients virtually design their dosage forms, including size, shape, and color and produce physical models before producing placebo-type coated tablets. The modeling tool allows manufacturers to get a firm grasp of the tablet designs they want to take forward in development.
(IMAGES ARE COURTESY OF BASF.)
Engineering and coprocessing are additional sophisticated tools that can help excipient suppliers enhance their materials to the high-quality level demanded by drug makers. "QbD initiatives require well-characterized and highly functional excipients to enable their implementation by drug formulators," says Deorkar. "Excipient technology development is centered on particle engineering and new chemical entities." For example, Mallinckrodt Baker recently developed "PanExcea" performance excipients, spherical homogeneous particles for immediate-release oral dosage forms and orally disintegrating tablet forms, using a proprietary particle engineering technology. This technology enables the precise tailoring of physical attributes such as particle size, distribution, porosity, and density in homogeneous particles containing multiple components, without changing the chemistry. "This reduces unfavorable attributes, while enhancing the functional characteristics of individual components through synergistic effects," says Deorkar.
Optimum functionality is a primary goal for many types of excipients. Take into account, for example, materials used in coating systems. The industry's basic needs in terms of functional coating are generally the same as they have always been. There is still demand for coating systems to aid in achieving various drug-release profiles while providing good flexibility, taste masking, adhesion, mechanical strength, and ability to withstand small variations in processing. Industry does not always agree, however, that these needs are actually being met. "Although the fundamental needs have not changed, needs are not currently being met satisfactory to the industry overall," says John Brown, marketing director at International Specialty Products (Wayne, NJ). "Those manufacturers have been able to work with what is available, but if you ask them they would tell you that it is not delivering 100% of what they are looking for. In some cases, it has been a product-driven market, so there is still a void. As the industry comes under a considerable amount of pressure because of cost savings, brand extension, and patent expiration, companies are looking to gain functionality."
There are several ways to increase the functionality of coating systems and other excipients, both for immediate-release and for modified-release purposes. The following describes a chemical and a statistical technique.
A polymer approach. Coatings are continuously improving in terms of the types of polymer systems, and excipient users and makers seek materials that will provide better performance at faster coating times. Hydroxypropyl methylcellulose (HPMC), for example, is one of the most commonly used polymers for tablet coating because of it forms films easily. However, the disadvantage with HPMC is that it has low flexibility, and brittle tablets with HPMC coatings may swell under the high humidity storage conditions present in some areas of the world. Swollen tablets then crack the coating. To avoid the effects of humidity, tablets must either be packaged in 100% sealed blisters, which require an expensive polymer or plastic foil as opposed to the typical PVC blisters that don't protect against humidity, or plasticizers must be added to the coating formula. However, as Folttmann observes, the disadvantage of plasticizers is that they may either migrate into the tablet core and interact with the active ingredient or they may migrate out of the film, outside of the tablet, making the coating brittle again.
In addition, aqueous coating polymers are spray dried, and the process time, energy, and amount of material required varies greatly, depending on the particular polymer used. For example, HPMC is diluted in water and then a plasticizer, color, and other materials are added before being sprayed onto tablets. However, only very low concentrations (~12%) of HPMC solution can be made, because when diluted in water, HPMC greatly increases the viscosity of the solution. Moreover, in a spray-drying coating process there is a lot of heat involved with the warm inlet air and the colder exhaust air and the energy that is used to remove the water. "When you work with a low concentration of a polymer such as HPMC, the spray process is rather long to get enough polymer onto the tablets, and you have to remove quite a lot of water to end up with a solid coating," explains Folttmann.
Improving polymers to reduce time, energy, and material is thus an important research area for coating formulators. BASF's instant-release coating material is a chemically new polymer (as opposed to a new mixture or a new coprocessed polymer) made of well-known polyethylene glycol (PEG) and polyvinyl alcohol (PVA) covalently bonded as a graft polymer, in which the sidechains of PVA are chemically bonded to a PEG backbone ("Kollicoat IR," see Figure 1). "Because PEG is part of the polymer and because it is chemically bound to PVA, it cannot migrate to the core nor escape the surface, and remains an extremely flexible film for all types of tablets," says Folttmann. Kollicoat IR can be diluted to concentration of up to 30%, so the spray process requires less water and a shorter period of time. As Folttmann observes, the challenge, as with many new excipients, is that companies are reluctant to try a formulation that has not been reviewed by regulators or monographed in a pharmacopeia. This year, Kollicoat IR received a draft monograph in PharmEuropa, which is expected to become final in the next year. (Visit the online exclusive article regarding the International Pharmaceutical Excipients Council's new efforts to reduce regulation hurdles for new excipients).
Figure 1: Grafted polymers, such as polyethylene glycol with polyvinyl alcohol, provide flexibility and reduce spray-coat time. (IMAGES ARE COURTESY OF BASF.)
A statistical strategy. When ISP entered the pharmaceutical coating segment of the industry in 2005, it set out to apply a statistical design of experiment (DOE) to create databases that would facilitate the design of coating formulations and to ascertain the ideal processing conditions for a given platform. "This approach has not been exploited to a high degree," says Stuart Porter, senior science fellow of film coating technology at ISP. "When you look at FDA's quality-by-design inititiatives, clearly using a statisitical DOE is one of the preferred approaches to creating the knowledge about the product. We have taken that same approach and created knowledge about our component of that product, which is the coating system."
The key variables of the database are the various properties of the coating systems, including mechanical strength, flexibility, adhesion, disintegration, dissolution, film roughness or smoothness, gloss, and cost. All responses are measured for each formulation in the DOE and the database is created as the ratio of ingredients and the types of ingredients in the formulation are manipulated. The database allows minimum values to be set in one area that needs to be achieved and how much the formulation can change to maintain those minimum values while improving the value in a different characteristic that is also important.
For example, consider the three important physical properties of coatings: strength, flexibility, and adhesion. "Making a coating with high film strength and high adhesion can be challenging because when you improve film strength, you have a negative effect on film adhesion and vice versa. So the challenge is to come up with a coating system that is a compromise between good enough film strength and good film adhesion characteristics that are required for that given application. Because typically when you manipulate the formulation, you gain something in one area and you lose something in another. There is a fine line between how much can you afford to give up in one area to gain something in another area," says Porter. "You can never say with a high degree of certainty that the formulation that seemed to have ideal properties for an application last week is going to be ideal for another similar application. There are so many variables. You might pick out a formulation today that meets 60% of the market needs and tomorrow it might be 20% and you have to come up with a variant of that formulation to meet those other 80%. The needs keep on changing. That's why having the database and the capability of manipulating it to meet these changing needs is so important."
The DOE database also factors in various process environments and the types of equipment. "The database gives us flexibility to make micro adjustments as necessary as we gain feedback information from customers. Having this information has allowed our regional labs to access this database and work at that customer interface level wherever they are. Anyone can access the database, the expertise is not centered within one or two individuals for ongoing business," says Brown. "Our interest educates our customers about what film coatings are and how they are tested, what they look like, and demystifying what these systems are really about, how they work, and why they work the way they do."
The technical knowledge gained from particle engineering, polymer science, and statistical design is of critical importance as companies strive to establish brand recognition, combat counterfeiting, and prevent medication errors. There are easily visible distinguishing markers such as edible ink branding and two-dimensional barcodes that can be placed on individual tablets. Other technologies include coatings of unique color. Colorcon's aqueous film coating "Opadry fx," for example, is a pearlescent pigmentation that applies light-reflection principles with both dark and light tablet cores (see Figure 2).
Figure 2: Using the basic principles of reflected light (top), Colorcon has developed pearlescent pigments (left). The effect of a subcoat color (e.g., light or dark tablet surface) influences the degree of pearlescence. (IMAGES ARE COURTESY OF COLORCON.)
Most anticounterfeiting efforts have focused on packaging, including radio frequency identification (RFID), holograms, and specialty labels. It is now equally, if not more, important to have on-dosage chemical and physical solutions built into the product. Chemical and physical taggants are covert technologies that can be added into a coating. "A chemical taggant may be an excipient that is not typically part of the coating formulation that acts as a marker within the coating at the parts per million or even parts per billion levels. "You can't detect that it's there through standard analytical technology unless you know it's there in the first place and you have specific systems that allow you to read it," says Schoneker. Physical taggants or microtaggants are particles that contain unique features or images. These microtaggants may be present at very low levels and can be easily assessed to determine authentic product versus a counterfeit. "In many cases, a counterfeiter wouldn't know these taggants are there. Or even if they knew they were there, they would have no ability to be able to make or get these unique microtaggants to try to counterfeit it," adds Schoneker. "It allows you to authenticate the products throughout the supply chain even if they have been repackaged or diverted."
Encryption. In 2000, the company NanoInk (Chicago, IL) was founded by licensing technology from the Northwestern School of Nanotechnology to place nanoscale features on certain substrates in a patterned manner. NanoGuardian, the brand protection division of NanoInk, used many of the aspects of that initial technology to develop pharmaceutical NanoEncryption, a state-of-the-art technology that places micron-scale and nano-scale security features on-dosage via manipulation of a finished product's coating. A proprietary "NanoEncrypter" typically located at the manufacturer's site, works to manipulate the coating of tablets (as well as capsules and vial caps) to place multitiered security features on each dose without affecting bioavailability, dissolution, and other performance characteristics. The technology has also been proven with uncoated tablets.
(IMAGES ARE COURTESY OF COLORCON.)
As Dean Hart, executive vice-president at NanoGuardian explains, the technology places three levels of security within the coating. The first is an overt feature, meaning it can be seen with the naked eye by authorities, pharmacies, investigators, and others just by knowing what to look for. The second level is a covert feature, which is a security mark placed within the easily visible overt mark. Detection of the covert mark requires the use of a handheld tool such as a microscope or jeweler's loupe.
The final security feature is at the forensic level and consists of specific "NanoCodes" placed within the coating. According to Hart, approximately 350 NanoCodes can fit in the width of a human hair, and NanoCodes can be associated with an unlimited amount of information. "A NanoCode can be associated with, for example, 30 different data points, and those data points can be manufacturing oriented such as batch number, lot number, production location and production date; product oriented such as strength and expiration date; or distribution oriented such as the state or country of distribution, and even the specific wholesaler or distributor to whom the product was sent. And once e-pedigree gets its legs, the NanoCode can be associated with the on-package RFID code, or two-dimensional barcode," says Hart.
"There are two things that pharmaceutical manufacturers need to accomplish to ensure protection of their products," says Hart. "The first is authenticity, which is easily done by NanoGuardian's overt and covert security features. The second is the ability to track and trace each product along the supply chain." NanoGuardian's forensic NanoCodes help manufacturers achieve that second 'need' by capturing an unlimited amount of distribution data on each dosage, thereby giving manufacturers the ability to trace each tablet, capsule, or vial back to its original packaging.
"When you look at the value of coatings, and the benefits of on-dosage security, that is where the real value of this technology comes into play," says Hart. "ePedigree will only tell you that this is the same piece of cardboard and piece of plastic that came from the plant all the way down the supply chain to the pharmacist. It doesn't really tell you that this is the same pill that was in that bottle to begin with. That is a risky assumption at the heart of ePedigree. But if you can take each dose and connect it to the on-package ePedigree technology that was used to track it through the supply chain, you remove that assumption and you have a closed loop of security that protects the medication from plant to patient."