Poor solubility remains a major challenge in formulation development. As the number of new chemical entities that are poorly soluble keeps increasing, formulation scientists are faced with the important task of addressing these solubility issues so that more compounds can be translated into clinically useful medicines. A popular approach to this problem is to use polymers as solubilizing excipients. 

 brought together a panel of industry experts for a special forum to discuss solubilizing polymers and the related formulation strategies for poorly soluble drugs. Participants include Michael Morgen, PhD, director of new technology at Bend Research; Brian Koblinski, strategic marketing manager at Dow Wolff Cellulosics; and Firouz Asgarzadeh, PhD, director of technical services, North America, pharma polymers & services at Evonik Corporation. 

Chemical classes and physicochemical properties

 Various polymers/copolymers can be used in solubility enhancement. What would you identify as key chemical classes for these excipients and the related properties that contribute to their function as a solubilizer? In what formulation types are they used?  

 Cellulosics, poly(vinylpyrrolidone) (PVP) and its copolymers, acrylates, and poly(ethylene oxide) (PEO) and its copolymers are some of the key classes of polymers that have been investigated as solubilizing excipients for oral formulations. Effective solubilizing polymers tend to be amphiphilic in nature, meaning they have both hydrophobic and hydrophilic sites that enable them to interact favorably with low-solubility (i.e., hydrophobic) compounds and yet disperse and dissolve in aqueous environments such as the gastrointestinal (GI) tract. The specific interactions of the polymer with itself, the API, and the aqueous medium can result in a range of solubilizing structures, including micelles, colloids, and ionic complexes. 

Solubilizing polymers are used in many types of formulations, depending on the route of administration, dose, API properties, and specific delivery challenges associated with the particular development program. For oral delivery, solid amorphous dispersions can be an enabling formulation approach for improving the bioavailability of Biopharmaceutics Classification System (BCS) Class II and IV compounds. Two common processes for making such dispersions are spray-drying and hot-melt extrusion (HME). Spray-drying can be used to form a monolithic dispersion particle or alternatively, the dispersion can be deposited onto a solid support to increase surface area and dissolution rate. Two-phase physical mixtures of polymer and crystalline API in a solid dosage form can be used to solubilize the API. For early scoping studies, liquid solutions of polymer (e.g., PEO) and the API may be valuable. In each case, the choice of formulation type and the manufacturing process will depend on the requirements of the specific drug-development program.  

 Cellulose-based polymers, such as hypromellose (HPMC) and hydroxypropyl methyl cellulose acetate succinate (HPMCAS, also known as hypromellose acetate succinate) have high utility in solid dispersions. Their safety and low drug reactivity make them an ideal candidate for most drugs. Spray-dried dispersions (SDDs) and HME are the most common technologies for solubilization used with cellulosic polymers. Cellulosic polymers maintain stable solid dispersions, inhibit API crystallization, and can promote supersaturation of the drug. Options in viscosity and substitution levels both with HPMC and HPMCAS help a formulator to optimize performance in solubility enhancement as well as in material processibility, which includes postprocessing SDDs and HME formulations into traditional dosage forms such as tablets and capsules. 

 The chemical structure and physicochemical properties of APIs and polymers play a major role in the formation of polymer-API solid solutions. Poly(meth)acrylates, cellulosic polymers and PVP are extensively used in solid dispersion formulation development. Each class of polymers contains specific chemical bonds that can interact with specific groups on APIs. HME, SDD, and coprecipitation techniques transform poorly-soluble crystalline drugs into an amorphous, metastable, higher-state-of-energy structure dispersed in a polymer matrix that is more easily solubilized, leading to enhanced solubility. Strong hydrogen bonding and ionic interactions between the amorphous API and the polymer would inhibit or retard the recrystallization of the API even with polymers that have low glass-transition temperatures (Tg's). Because there is a myriad of API structures with different physicochemical characteristics, there is not one class of polymers that would be considered better solubilizers than others. It is essential to select appropriate polymers for screening studies based on a good understanding of both the polymer and drug structures and the possible interactions they may have. 

 What factors determine the type of pharma polymer to use in a given formulation to improve solubility? Can you provide a specific example to illustrate the decision points used in a challenging formulation, including any relevant data?  

 When selecting solubilizing polymers, the performance, stability, and manufacturability of the associated formulation must all be considered. The chemical and physical properties of the solubilizing polymer affect all three of these attributes; hence, it is often necessary to balance polymer properties to achieve the optimum solubilized formulation. Usually, the properties of the API and the requirements of the development program (e.g., dose) will result in greater emphasis on one or two of these three formulation attributes. 

Ideally, the solubilizing polymer will interact with the API to sustain elevated API concentrations in the GI tract in one or more high-activity species (e.g., freely dissolved drug, micelles, and colloids). For APIs that are particularly prone to precipitation into a low-energy form, significant polymer/API interaction is especially important. For many APIs, polymers that have a substantial hydrophobic interaction with the API are preferred. HPMCAS is one of the more broadly useful dispersion polymers for forming and sustaining high-energy species in aqueous media with BCS Class II and IV compounds. 

Both the chemical and physical stability of solubilized formulations are important. Of the two, chemical stability tends to be more API-specific. Solid-state physical stability is usually an important consideration for solubilized formulations, especially when the drug is in the amorphous state. A key driver for good solid-state physical stability of amorphous forms, such as polymeric dispersions, is low molecular mobility, which can be achieved by choosing a dispersion polymer that has a high Tg. A number of common solubilization polymers, such as PVP and its copolymers and cellulosics, have high Tg in their dry state. Water, however, can plasticize materials and reduce the Tg. Polymers with low-moisture uptake as a function of humidity, such as HPMCAS, often impart better physical stability to amorphous drug forms in the solid state under ambient storage conditions than the more hygroscopic polymers. A high Tg is less important for physical stability when the API and polymer are miscible, which is often the goal for HME formulations. 

Manufacturability is an important consideration when selecting solubilization polymers. For spray drying, high solubility and low viscosity in the volatile organic solvents used during processing are important. HME processing requirements are somewhat different, requiring good thermal stability, especially when formulating drugs with high melting temperature (Tm). In addition, the miscibility of the API and polymer is often desirable in HME processing to achieve a single dispersion phase. 

 The chemical structure of the API as well as the technology used to achieve improved solubility impact polymer choice. SDD and HME are two common technologies used to create solid dispersions to improve solubility. Each technique has its own set of polymer parameters best suited for use in the technology, yet the overall goals for both methods are to render the drug amorphous, inhibit drug crystallization, and to maximize drug load in the formulation.  

Characteristics of polymers best suited for spray drying include the ability to form a sprayable polymer-drug solution. Polymers that result in low-solution viscosity will facilitate higher concentrations of drug and polymer in the solution, thereby reducing solvent usage and increasing formulation versatility.  

To be suitable for HME, a pharmaceutical polymer must be melt processable at conditions that do not degrade the formulation components. Polymers with low Tg as well as a broad thermal-processing window are well suited for HME; however, the Tg must be high enough to prevent recrystallization at storage conditions. The polymer must also have good crystal nucleation inhibition to maintain the API at supersaturated levels upon dissolution. Due to a relatively higher polymer content in many HME formulations, polymer safety during processing (i.e., no toxic degradation products) and in the final formulation is also critical. 

 Polymers used for solid-dispersion formation should have reasonably high Tg's to allow the stabilization of the amorphous API structure 

molecular motion restriction (i.e., the glassy state) at storage conditions that are usually below the finished product Tg. Polymers with lower Tg's have been shown to form stable solid solutions when strong hydrogen bonding or ionic interactions are formed between the polymer and the active. The strong hydrogen bonding and ionic interactions contribute to  the formation and stabilization of solid solutions firstly, by breaking the crystal lattice of poorly-soluble, highly crystalline drugs, and secondly, by delaying the recrystallization as the molecularly dispersed API would prefer to stay bound to the polymer.  

Another consideration when using melt extrusion for preparation of solid dispersions is that the polymer Tg should be sufficiently low to allow acceptable processing temperatures minimizing polymer and/or drug degradation. The cationic amino methacrylate copolymer (Eudragit E, Evonik) forms solutions with the anionic drug ibuprofen due to strong hydrogen bonding and ionic interactions at extrusion temperatures as low as 60 °C. Although the Tg's of ibuprofen/Eudragit E solid solution extrudates are as low as 10 °C to 20 °C, they remain amorphous and stable at room temperatures due to the strong hydrogen bonding and ionic interactions. API melting during melt extrusion is not a requirement but helps with solid-solution formation. Solid solutions of drugs with melting point as high as 250 °C to 300 °C is possible when such strong interactions can be formed between polymers and the drug as is the case for sugar and water (solute/solvent) where sugar is not needed to melt in order to be dissolved in water. 

Can predictive modeling be used in excipient selection of a solubilizing polymer? If so, can you explain the modeling and the related variables used in the model?  

 A range of predictive physical models are helpful in selecting solubilizing polymers. Such models are most valuable when used in conjunction with measured physical properties of the API, the polymer, and/or the formulation. In particular, we often use models to estimate oral absorption based on key parameters, such as API dose, solubility and supersaturation values, API partition coefficient into bile salts, and API dissolution and precipitation rates. Several of these parameters depend on the choice of polymer. In particular, the time profile of the API supersaturation level is often heavily influenced by the choice of polymer and can dramatically affect absorption and bioavailability. These parameters are typically measured 

and then used in predictive models. An important caveat is that it is notoriously difficult to accurately predict certain 

 parameters, such as API precipitation rate based on 

 measurements. Other types of models that are sometimes employed include solubility parameter approaches to predict interactions between APIs and polymers, including estimates of API solubility in a polymer matrix. Although such predictions can be useful, it is sometimes faster and more accurate to make the measurements than to do the calculations. 

 Predictive modeling can be used to calculate polymer–API interactions that may occur. In addition, tools, such as solubility parameters, can be used to establish API solubility in the selected polymer. Hansen solubility parameters are often used in this regard as a screening tool for drug-polymer compatibility, however, they should only be used as a guide in conjunction with preformulation data. 

 In a conventional empirical formulation development approach, various qualitative and quantitative combinations of drug and polymers are melted, spray-dried, or film-casted from organic solvents in numerous experiments to identify appropriate solid solution/dispersion formulations. Such empirical development methodologies are time-consuming and require significant amount of drug as well as costly analyses. Predictive tools to identify solvents for polymers based upon solubility parameters and molecular interactions (e.g., hydrogen bonding and ionic interactions) have been used for several decades in paint, polymer, and organic-chemistry industries. These predictive tools afford faster systematic screening of formulations and processing conditions at the early stages of solid-dispersion product development, independent of the preparation technology used.  

One such tool developed by Evonik is MemFis (Melt-Extrusion Modeling and Formulation-Information System). The MemFis model uses well-established polymer and organic-chemistry group contribution theories to estimate Hansen solubility parameters of drug molecules and polymers. In MemFis, the calculations of more than 50 chemical group contributions and the effects of polar (i.e., dipole moments) as well as 40 different hydrogen-bonding interactions on solubility parameters are considered. MemFis enables the selection of initial solid-solution/dispersion formulations and melt-extrusion processing conditions without API consumption. It reduces the number of experiments by bringing quality into formulation development in a systematic rather than empirical approach targeting appropriate experiments. Other analytical tools, such as Raman mapping, differential scanning calorimetry, and atomic force microscopy, can allow early detection of solid-solution formation or any recrystallization effects. 

 Quality by design (QbD) is an overarching consideration in drug development. With respect to solubility enhancement, what are the critical quality attributes and/or critical process parameters important in excipient selection? 

 Recently, pharmaceutical companies, excipient providers, and CRDMOs (contract research/development/manufacturing organizations) have launched significant initiatives to bring QbD principles to the selection and design of the polymer, the formulation, and the process space. With respect to the polymer, critical quality attributes might include molecular-weight distribution and chemistry attributes, such as the ratio and sequence of different monomeric units and/or the number and substitution pattern of hydrophobic groups on the polymer backbone. There are instances in which relatively small differences in chemistry can significantly affect the performance of the polymer and the formulation. In some cases, the impurity profile of the polymer can also be critical to the performance. 

Typically, a number of critical parameters on the process side will influence the choice of excipients. Depending on the process, solvents, and solution temperatures may be selected based on solubility of API or its compatibility with the solvent, which can in turn influence the choice of the polymer. Likewise, process- time–temperature profiles can be critical process parameters, particularly for the choice of HME excipients, to ensure adequate mixing for complete dispersal and dissolution of the API into the heated polymer matrix if a solid solution is desired. 

 Selecting the right excipient with control of the critical quality attributes is crucial to a robust formulation. A QbD approach to drug development helps the final drug product to have the desired therapeutic effect on a consistent basis. In solubility enhancement, excipients play the role of stabilizing the drug and keeping it in the desired state to achieve the maximum drug release and concentration sustainment. A QbD study with an excipient, for example HPMCAS, will look at characteristics of the polymer, such as acetyl and succinyl substitution using a design of experiment study to cover the experimental space to find the enhanced substitution levels for solubilization of the specific drug. Through studies done at Dow, we have found some drugs, such as phenytoin, are very sensitive to changes in polymer substitution levels and, therefore, require tight control around the enhanced values for consistent performance. Other less sensitive drugs can tolerate a wider range of substitution values while maintaining performance. A QbD program, in cooperation with the excipient manufacturer, can help formulators develop a robust and therapeutically efficient drug product. 

 When selecting excipients for solubility enhancement, excipient physicochemical properties such as morphological characteristics, aqueous/pH solubility, molecular weight, crystalline structure, porosity, density, and viscosity are amongst the critical quality attributes (CQAs) that should be evaluated. The impact of selected CQAs based upon the risk-assessment survey on the properties of the final product should be studied and well understood. Excipients in a solubility-enhanced formulation should not be considered as fillers or part of the binding matrix anymore because they contribute to the performance of API that otherwise does not have any absorption and bioavailability. The critical process parameters (CPPs) are process specific attributes. For solubility-enhancement applications,  melt extrusion and spray drying are the most commonly used technologies. The CPPs for melt extrusion are the screw speed, extrusion temperature, feed rate, glass-transition temperature of the drug-polymer mixture, and melt viscosity. For spray drying however, parameters such as spray rate, percent solids content, size, and scale of the spray dryer, nozzle size and temperature in the expansion chamber should be considered.  

Articles

Pharmaceutical Technology brought together a panel of industry experts for a special forum to discuss solubilizing polymers and the related formulation strategies for poorly soluble drugs.

Advancing Polymers for Solubility Enhancement

High efficiency in unit operations is a prequisite for achieving overall improvements in solid-dosage manufacturing. The authors examine recent advances in equipment design and operation in spraying, drying, and mixing to  improve the tablet-coating process. 

Cost is a crucial issue for pharmaceutical companies, generic-drug manufacturers, and CMOs, which must be attentive to overall operational costs of equipment as well as upfront capital costs. High-efficiency processing in solid-dosage manufacturing is a desired goal, and tablet coaters and granulators have undergone technology improvements to achieve continuous improvement in these operations. 

Improvements in solid-dosage manufacturing

To evaluate improvements in solid-dosage manufacturing,  one must examine the advances in equipment design and operation in spraying, drying, and mixing to improve the overall tablet-coating process. Highlights of such advances are further described.  

 Improvements to tablet-coating technologies are helping pharmaceutical manufacturers to achieve higher uniformity and waste reduction. These improvements are mostly due to mixing-system advances as well as pan and airflow configuration. Tablet coating consists of three main steps: spraying, drying, and mixing. Each step must be calibrated with the others to optimize the entire process. 

 Spraying equipment includes the nozzle types, number and type of guns, and gun-to-gun spacing. Process parameters include spray rate, gun-to-tablet-bed distance and angle, atomization air pressure, and pattern air pressure. Spray-gun nozzles are key to efficient coating, and nozzles that create an oval spray pattern and a spray angle of 50° to 60° work best. The configuration of the spray boom will dictate the amount of spray-cone overlap. A slight overlap of the spray cones from each nozzle may be desirable for consistent coverage; however, too much overlap will lead to localized overwetting of the tablet bed. In most cases, the gun-to-bed distance will range from 6 in. to 10 in. although the actual distance depends on the force of the atomization air pressure and pattern air pressure on the coating-pan size.  

 Drying of the coating suspension takes place during the atomization and when spreading on the tablet surface. The temperature of the inlet air, volume flow and humidity of the inlet air, and the degree of pan perforation control drying. These parameters must be controlled in a way that prevents overwetting but does not cause spray-drying. The way the air moves through the coating pan also influences drying. Most coating pans draw air from the top of the pan and exhaust it to the side. Others place both the inlet and outlet at the pan's base. No matter where the inlet and outlet are, the goal is to handle the air in a way that minimizes turbulence and excessive heat in the spray zone. A balance must be struck between the temperature and volume of the inlet air and the spray rate. 

 Mixing is a prerequisite for a homogeneous and uniform coating. Ideally, the pan's action will mix the tablets in a way that exposes each to the spray equally. Doing so depends on pan geometry and the use of baffles, spirals, lifting bars, or other components. Many common pans have a diameter that exceeds their length. This ratio can create a tablet bed too deep for effective mixing. It is not uncommon to find dead spots in the middle of these tablet beds. Such dead spots can cause overwetting and the formation of clumps or twins, which may damage the tablets. 

To break up or prevent clumps and dead zones, some pans are fitted with a device called a baffle or shovel. The shovel is fixed within the coating pan, so as the pan turns, the tablets contact the shovel, steering them outward. Although the shovel insert may improve mixing, it can increase the risk of tablet breakage. An alternative approach is to use a pan whose length exceeds its diameter and that incorporates helical baffles for gentle tablet mixing. The longer pan creates a shallow tablet bed that is free of dead zones. The upper and lower helical baffles expose all the tablets to the spray equally. This configuration enables higher spray rates, which shortens the time required to coat tablets in each batch. 

The role of coater design in manufacturing

Once pharmaceutical manufacturers understand the basic elements of tablet coating, they can determine which tablet- coater features best suit their solid-dosage product. For example, relying on a coater whose coating pan length exceeds its diameter creates a shallow tablet bed that promotes tablet exposure to the spray. It also allows the installation of more nozzles over the bed than is possible in conventional pans. This combination exponentially improves coating uniformity. There is a limit to the number of nozzles that should be added, however. Manufacturers must weigh the benefit of adding nozzles against the risk of overwetting the tablet bed. It is best to use enough nozzles to cover the bed while avoiding or minimizing overlap. 

Airflow must also be evaluated. Conventional coaters have top-to-side airflow, so high-velocity warm air passes through the spray zone. That implementation of the air flow causes turbulence and the possibility of spray-drying the coating droplets. Pharmaceutical manufacturers can reduce those effects by adjusting the airflow, temperature, and spray rate. That correction, however, may slow the coating operation or increase the amount of wasted coating solution. 

Minimum air turbulence and improved coating applications can be achieved by using a pan with an inlet and outlet that span the pan's base. This design improvement also allows an improved control over tablet-bed temperature. Additionally, that control yields faster spray rates and reduces coating times by as much as 45%. 

Companies using both coating pan designs have found that pans with top-to-side airflow are up to 85% efficient. This result means approximately 15% or more of the spray is deposited within the coating pan on the guns and spray boom or in the exhaust. Designs using base-to-base airflow, which pull the spray onto the tablet bed like a vacuum, can reach approximately 98% efficiency. They also shorten overall coating time because they enable higher spray rates without overwetting the tablet bed. 

In applications requiring thick tablet coatings, the tablet bed can grow by one-third or more. This formulation requires an adjustment of the gun-to-bed distance during the process. When tablet coating involves potent substances, manufacturers can consider automating the movement of the nozzles, spray boom, or both. This feature eliminates the need to open the coating pan, thereby increasing efficiency and safety. 

Finally, manufacturers should note how their coating pan mixes and handles the tablets. Homogenous mixing promotes content uniformity. Pans equipped with helical mixing baffles constantly move the tablets back and forth across the pan, thereby eliminating dead spots.  

Researchers have performed various scientific studies in high-efficiency coating in solid-dosage manufacturing. These studies provide guidance for tablet-coater process improvements (1–6). 

Scale-up effects on tablet abrasion during pan coating. 

 A 2006 study investigated the influence of production scale-up on tablet abrasion in a pan coater (1). It examined how batch size during scale-up can affect the abrasion and edge-splitting of flat-faced tablets. The researchers looked at the weight loss of white tracer tablets mixed with a batch of blue-coated tablets in a laboratory-scale pan coater and a pilot-scale pan coater as a function of different pan speeds and mixing times. They observed that increasing batch size caused a decrease in weight loss due to less damage of the tablet edges. The researchers determined that a higher number of tablet impacts at the pan wall at laboratory scale compared with pilot scale might account for this outcome. This effect runs counter to the common belief that increasing batch size in scale-up leads to a higher abrasion or tablet damaging (1).   

Raman spectroscopy as a PAT tool in active coating. 

Active coating is a film-coating application in which the drug's active ingredient is included in the coating layer. It presents manufacturers with the challenge of achieving the right amount of coating and uniformity on each dosage. To ensure the quality of each dosage, manufacturers can benefit by developing process analytical technology (PAT) that can monitor the coating process and detect the end of the coating cycle. In one study, researchers performed coating experiments using the drug diprophylline (2). They used a pan coater to coat placebo tablets and tablets containing diprophylline. During active coating, researchers recorded Raman spectra in-line. These spectral measurements were compared with the average weight gain and the amount of coated active ingredient at each point in time (2). 

The chemometric model they created using Raman spectroscopy was tested by monitoring more coated batches. The research team also studied the effects of pan-rotation speed and working distance on the Raman signal and studied the resulting effect of the chemometric model. Using Raman spectroscopy as a PAT tool, they were able to determine the amount of active ingredient in the film when coated onto cores of placebo tablets and tablets containing the same active ingredient. Researchers also determined that this method can be used when changing the process parameters and measurement conditions within a restricted range, making it an appropriate PAT tool (2). 

Comparing laboratory and production coating spray gun for scale-up. 

In a scale-up study, researchers investigated a laboratory spray gun and a product spray gun (3). They analyzed the influence of the atomization air pressure, spray-gun-to-tablet-bed distance, polymer-solution viscosity, and spray rate. The spray guns were compared based on spray width and height, droplet size and velocity, and spray density. Researchers measured spray density, droplet size, and velocity with a phase Doppler particle analyzer (3). This study gave the investigators basic information for the scale-up settings from the laboratory and production spray guns. Both were comparable with respect to droplet size and velocity, and the scale-up of droplet size can be performed by an adjustment of the atomization air pressure. Scale-up of droplet velocity can be achieved by adjusting the spray gun to tablet-bed distance. The result of the study was that the researchers' statistical model and surface plots were powerful and convenient tools for scaling up spray settings if the spray gun was changed from a laboratory spray gun to a production spray gun (3).  

Continuous dry granulation is an established process in the pharmaceutical industry. Today, it is not only applied for moisture- and temperature-sensitive materials but also for large-volume solid-dosage products. In comparison with classical wet-granulation techniques, a sophisticated drying system is not required for processing. This elimination of the drying system avoids large investments for production equipment and space and lowers manufacturing costs. An additional benefit to having an one-unit operation is its suitability for installation in a one-floor operation. The dry granulator can be fed with a single intermediate bulk container (IBC). To enable a continuous process, an enlarged power-feed hopper can be used with a level sensor and adequate holding capacity to enable the change-out of additional IBCs without interrupting the process.  

On the discharge side, a simple plug-flow pneumatic conveying system can be used to transfer the resulting granulation into a receiving IBC for future blending and processing. This reduction in  handling equipment can further reduce the capital costs with a dry-granulation system. 

Furthermore, for large-volume throughputs, the fast roller-compaction process is paramount to efficient processing. This efficiency enables the production of different products and product batch sizes with one single machine (4). The market already offers various dry granulators, which can be described by the arrangement of the two compaction rollers. They can be mounted horizontally, vertically, or on an incline. 

Depending on the supplier, the rollers differ in width, diameter, and surface properties. Furthermore, roller compactors are distinguished between fixed-gap and moveable gap compactors, whereas the moveable roller compactors are state of the art. Only moveable roller compactors, however, ensure homogeneous ribbon porosity at constant compaction pressure.  

The granulation step, where the ribbons are transferred into final granules, is usually integrated in the roller-compaction equipment and is performed in one or two steps (5, 6). With this in mind, manufacturers introduced a dry granulator with an electromechanical roller drive and massive roller shafts mounted in a horizontal manner. 

With this newly developed machine, minimal time is needed to achieve a steady state during process start-up, and parallel gap is ensured during the whole production time. The proportional-integral-derivative (PID) loop control minimizes the gap deviations during processing and enables constant granule porosities. The granulation step is achieved using a conical sieve, which gently transforms the ribbons into final granules even at high material throughputs. Due to different sieve setups, the desired particle-size distribution can be obtained. 

The aim of the following study is to show and prove the functionality of this type of sophisticated dry granulator. 

 A powder mixture (1:1 ratio) consisting of lactose and microcrystalline cellulose was used for roller compaction. For lubrication, 0.5 % magnesium stearate was added. The excipients were premixed in a bin blender. The homogeneous blend was roller-compacted at different compaction forces and different sieve setups. A smooth master roll and a grooved slave roll of 100-mm width were used for the compaction trials. Sampling was performed after the process start-up when steady state was reached. Final granules were manually subsampled and analyzed in duplicate by mechanical sieving. 

The impact of the compaction force on the final granule particle size was analyzed at 2-rpm roller speed, 300 rpm for the 1.5-mm rasp sieve, and a gap width of 2.5 mm. The process began with an activated PID loop control for the feeding system. Steady state was achieved within 40 seconds with a constant specific compaction force and a constant gap width. Thus, a minimal material loss could be detected due to the quick loop control. 

During processing, the compaction force was increased step-wise, so that the next force level was quickly achieved within seconds. Deviations of the specific compaction force were below ± 0.1 kN/cm and ± 0.1 mm for the gap, respectively. Thus, both parameters could be considered constant during processing. 

Granule particle size increased with higher compaction force levels. After granulation, through a 1.5-mm rasp sieve, the amount of fines (particle size < 100 µm) ranged from 39% for the granules compacted at 5 kN/cm to 11% for granules prepared at a 15-kN/cm compaction force. Compaction at such a high force level led to a higher amount of coarse granules (> 2000 µm). Therefore, a smaller screen size between 1 mm and 1.5 mm is recommended to minimize this large granule fraction. 

Material throughput during roller compaction can be increased with a larger gap width. It was reported in the literature that a larger gap width at a constant compaction-force level leads to finer granules (4). This effect could not be observed when compacting the powder mixture at 10 kN/cm.  

At 2-rpm roller speed and 300-rpm sieve speed (1.5-mm rasp sieve), comparable granule particle-size distributions were obtained although the gap width was increased from 1.5 mm up to 3.5 mm. A homogeneous application of the compaction force over the whole roller width could be one reason for the similar granule size. Thus, material throughput could be easily increased without a change in granule properties. 

The applied compaction force mainly affects granule particle size. Secondly, the setup of an integrated granulation unit determines the final particle-size distribution. With increasing screen size, coarser granules are obtained. 

The rasp sieves with 1.5-mm and 2-mm screen size led to similar granule particle-size distributions at 300-rpm sieve speed. In comparison, the 1-mm rasp sieve led to finer granules with higher amount of fines. Finally, all three screen types led to acceptable amounts of fines due to the gentle cutting behavior of the rasp sieve during granulation. The choice of the right screen size makes it possible to influence the final granule particle size distribution. 

A further possibility to vary the sieve setup is the alteration of the sieve-rotor speed. In contrast to classical rotating-sieve systems, conical sieves offer a high material throughput already at low sieve speed values. To evaluate the sieve-speed impact on final granule size, compaction was performed at a 10-kN/cm specific compaction force, 2-rpm roller speed, and increasing sieve speed values for one screen size (i.e., 1.5-mm rasp sieve). 

With higher sieve speed, the amount of fines decreased. This result can be explained by the fact that, with higher rotor speed, the ribbons need less time to pass the screen. Less friction occurs during granulation and leads to a lower amount of fines. Therefore, altering the sieve speed is another possibility to adjust the desired particle-size distribution of the final granules. 

This study proves the functionality of the new roller compactors. It was possible to precisely produce a representative placebo granule formulation with negligible material waste during process start-up. Furthermore, the study shows that a suitable sieve setup offers the possibility to achieve a desired granule size by altering screen size and sieve speed. 

Recent advances in equipment design and operation in spraying, drying, and mixing can improve the tablet-coating process.

Continuous Improvement in Tablet Coating and Dry Granulation

This article provides an overview of I Holland's tableting science anti-stick research (TSAR) project, which the company is conducting in collaboration with the University of Nottingham in the United Kingdom. The TSAR project seeks to understand why certain formulations stick to tablet tooling, a major problem often encountered by tablet manufacturers.

Problems during tablet manufacturing often result in process downtime and higher operating costs. Some of these problems can be minimized or eliminated with proper maintenance and storage of tablet tooling. 

 spoke to experts at I Holland about the causes of common problems such as tablet weight variation, hardness or breakage issues, capping, picking, and sticking, as well as a seven-step process for tool care. 

I Holland representatives also discussed the company's research collaboration with Nottingham University's School of Pharmacy in the United Kingdom, which seeks to understand why certain formulations stick to tablet tooling, a major problem that is often encountered by tablet manufacturers. The aim of this joint project is to develop a predictive tool that will enable the identification of the best coating solution for formulation-sticking issues without the need of carrying out full-scale trial-and-error experiments with several anti-stick coatings. 

 Tableting science is part of I Holland's core service offering. It encompasses many aspects of our R&D capability, including work with academic and technical partners on scientific research projects that help us to improve our understanding of why a punch or die performs well. For example, for years many tooling manufacturers have polished punches to an optimum mirror finish because they know it helps the punch to perform more effectively, but no one really understood why this was the case. Punch and die manufacturers are essentially engineering companies and often have a reluctance to become involved in wider tableting issues.  

Our investment in tableting science will help tablet manufacturers to reduce expenditures that can be associated with poor tooling performance further down the line by eliminating many issues before the punch or die hits production. For example, 'sticking' is a major tablet-production issue that we are trying to tackle through our work with the University of Nottingham on the tableting science anti-stick research (TSAR) project. We hope to deliver a predictive tool that will remove the need to undertake expensive coating trials to determine the best coating solution. 

What are the common problems encountered in tablet manufacturing?  

 There are many common problems encountered in tablet manufacturing. Some of the most common of these are listed below. Each of these problem areas may have several potential causes, but brief overviews of the main ones are summarized below:  

 The most likely cause of this problem is the extensive variation in punch working lengths, which can often be due to worn punches or sticking/picking that can cause granules to build up on the punch face and result in nonuniform punch lengths.

Picking refers to when a compressed granule adheres to the detail (i.e., embossing) on the punch face. This problem could be due to inappropriate embossing design, worn tip faces, insufficient compaction force, or granulation issues such as excessive moisture or insufficient lubricant.

Sticking is defined as general granule adherence to the punch-tip surface. The same causes as for picking may apply. Additionally, inappropriate tablet profile may have an impact on inadequate tablet hardness and density.

Capping is the laminar separation of the tablet body or cup and is often caused by air entrapment in the body of the tablet.

 This problem could be attributed to poor embossing design (i.e., too small or too shallow), worn punch faces due to abrasive formulation, or excessive polishing.

These issues are often caused by uneven punch lengths across a set, incorrect binding agents in the formulation, or capping due to air entrapment. 

Other tooling related problems exist such as:  

 Punch and die manufacturers should be able to provide training on these issues and how to solve them (1). 

What are the solutions to these problems?  

 Depending on the exact causes of each of the problems previously described, there are several potential solutions. As a guide, following a simple seven-step process for tool care and maintenance can help to minimize the potential occurrence of most tableting and tooling issues (2). The seven-step process is a logically planned and professional approach to tooling maintenance and storage as summarized below:  

When tooling is removed from the tablet press, it should be thoroughly cleaned and dried to remove any oil or product residue, especially from difficult-to-reach areas such as embossing and keyways. 

 Punches and dies should be visually inspected under magnification for signs of damage, wear, or corrosion, and to validate the cleaning process. This assessment will establish whether the production process is running well or not, thereby giving clues to problems with the tablet press or tooling itself and if any tooling maintenance is required. 

 Light surface wear, corrosion, and damage on tooling can be repaired and polished to a useable condition. Worn tips can result in poor quality tablets and inferior embossing definition that can lead to picking and sticking. Repair should be carried out by well-trained and experienced maintenance technicians to ensure that the tooling does not exceed tolerance limits. 

 Measuring is essential after repair to ensure that critical tooling dimensions have been maintained within an acceptable working tolerance. Measuring should be carried out at regular intervals even if repair has not been necessary, to check for natural wear during the compaction process. The essential measurement is the critical working length of the punch as it controls tablet thickness, weight, and dosage.

 Controlled, light polishing on a frequent basis will ensure that tools are maintained to a smooth finish, thereby helping to maximize tooling life and reduce problems such as sticking and capping. 

 Lubrication is important to protect, preserve, and aid smooth operation of the tooling. A range of oils and greases can be recommended for different applications, such as preservatives, or for lubrication purposes.

Tooling storage and transportation should be specifically designed to maximize security and safe handling to minimize damage and deterioration. 

Could you tell us more about the TSAR project, for which you are collaborating with the University of Nottingham?  

Since the launch of our PharmaCote range of punch and die coatings more than five years ago, I Holland has been increasingly called on to solve sticking issues within the pharmaceutical sector as tablet manufacturers realize that these problems can be eliminated without reducing product yield and investing in expensive magnesium stearate systems. The traditional way of troubleshooting a sticking problem would have been to supply a customer with a test set of tools containing many different punch and die coatings. A full compression trial would be carried out at the customer's site to ascertain the coating that would most effectively solve the sticking problem. This approach involves a significant investment for the customer in the tooling as well as in time. 

The aim of the TSAR project is to develop a predictive tool that will allow us to identify which punch and die coating is most likely to solve these sticking issues, thus removing the need to carry out full-scale compression trials with all of the anti-stick coatings. The development of the predictive tool will not commence until we have gathered sufficient interaction data from many different excipients and active ingredients. This work is currently in progress as we are testing several samples supplied by our customers. 

We aim to use newly developed multivariant analysis techniques linked to nanoscale surface chemistry and morphology techniques such as atomic force microscopy (AFM), time-of-flight secondary ion mass spectroscopy (ToFSIMS), Raman spectroscopy, contact angle measurements, X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), and laser profilometry. Once the data are gathered, we will use a principle component analysis tool to allow us to group the different excipients/active ingredients. Only after this process, will we be able to start the development of the predictive tool. 

We are currently halfway through the two-year project and have spent the first year solely gathering data from various products supplied to us by different customers. The most utilized piece of equipment to date has been the AFM, which allows us to quantitatively map, at the nanoscale, adhesion on PharmaCote coated tablet punches using single drug/excipient particles. The low adhesion force measurements (nN) gathered within the AFM indicates the level of Van der Waals forces that are present. We are also changing the humidity and temperature within the testing environment to gather data on capillary forces that are present. Only when all the ingredients of the formulation are tested in this analytical way, do we move the formulation into a production environment and compress tablets using the same PharmaCote coated tooling.  

This 'real world' checking allows the results of the analytical testing to be verified in a production environment and gives the customer the reassurance that they are purchasing the optimum solution for their specific problem. It cannot be stressed enough how each sticking problem is unique and can vary significantly from site to site, press to press, and product to product, which makes laboratory compression testing vital. 

1.  Eurostandard Educational Collection 2010 Edition. 

The tableting science anti-research (TSAR) project seeks to understand why certain formulations stick to tablet tooling.

Tackling Common Problems in Tableting and Tooling

Managing excipient variability is an essential element in designing and manufacturing robust solid oral drug products and is an integral task in when applying quality-by-design (QbD) principles. The article examines factors in assessing excipient variability, the associated challenges developers need to address to design and manufacture solid oral drug products, and solutions for such challenges.  

Excipients play a crucial role in a formulation, and as part of the formulation, influence the quality of the final drug product. Managing excipient variability is an essential element in designing and manufacturing robust solid oral drug products and is an integral task in applying quality-by-design (QbD) principles. 

 examined excipient performance in QbD in a webcast (

) in 2012. Participating in that webcast were Catherine Sheehan, director of excipients at the US Pharmacopeia, Ian Robertson, global QbD manager at Colorcon, Chris Moreton, vice-president of pharmaceutical sciences at FinnBrit Consulting, and Greg Amidon, research professor of pharmaceutical sciences in the College of Pharmacy at the University of Michigan and chair of the USP Excipient Performance Expert Panel. In this article, Robertson offers insight on managing excipient variability in a QbD paradigm. 

 What are key considerations in assessing excipient variability and what are the associated challenges developers need to address to design and manufacture solid oral drug products?  

 Understanding the effects of normal excipient variability is important to ensure that potential risks to drug-product quality are effectively managed. With an increasing focus on QbD, both innovator and generic-drug developers will be required to demonstrate excipient risk management in relation to the drug products' critical quality attributes. So, while it is the developer's responsibility to demonstrate robust formulation design and manufacture, it is important that all stakeholders collaborate early in the product lifecycle to ensure mutual success. Often, knowledge and tools to proactively assess the effects of excipient variability upon drug-product quality are available. Of course, this not only provides sufficient development but, importantly, supports implementation of an effective control strategy for subsequent commercial manufacture. 

So one may ask, why are excipients variable, and what are the sources of variability? Well, excipients used within the pharmaceutical drug products are diverse in terms of their chemistry, origin, manufacture, and also control. Broadly speaking, we could consider two classes of excipient products. Those described as natural or naturally derived, and those described as synthetic or semisynthetic. The natural or naturally derived excipient products and factors, including the crop source along with environmental variables, such as the growing and processing conditions, can all affect the physicochemical properties of the resultant excipient product. Even for synthetic or semisynthetic excipient, differences in the feedstock, such as the organic and inorganic components from crude oil or gas, along with variability in chemical processing, will all contribute to the overall variability of the excipient product itself. 

For an individual manufacturer of an excipient product, there may be lot-to-lot variability of the physicochemical properties. Often, a manufacturer may make related products, such as different physical or chemical grades, or even supply different industries. Therefore, different manufacturing campaigns may be adopted, which can lead to variability associated with switchover, start-up, or shutdown upon a single production line. 

Indeed, between the multiple manufacturers of an excipient, it is likely there will be differences in the raw materials and the production process used, the scale of manufacture,  and location, all which can contribute to the variability of an excipient product's physicochemical properties. 

I think it's also important to recognize the variability in the controls used. Although excipients are required to meet the appropriate pharmacopeia standards, there may  be differences in the excipient specifications from vendor to vendor. This can include the ranges specified within standard tests as well as the inclusion of noncompendial physicochemical property tests. 

Along with the specified parameters, it is important to also consider both unspecified parameters as well as nonroutine parameters. The variability of unspecified or unreported parameters, could impact drug-product performance depending upon its design and intended use. Although unreported, these properties may be measured by the manufacturer as part of its control strategy. In addition, excipients can vary in what is termed nonroutine parameters (e.g., residual reactants and residual catalysts). Variation of these parameters may not be commonly measured by the manufacturer. 

So in the majority of cases, robust drug products are successfully developed and manufactured to manage such excipient variability. Failure, however, to understand and control excipient variability has indeed led to some serious quality issues. 

FDA, for example, has spoken publicly about excipient variability and its relation to drug-product recalls from the market. It is clear that some existing development and manufacturing practices can fail to ensure that medicines of the appropriate quality standards that are routinely produced. Furthermore, demonstrating quality by testing does not prevent these substandard drug products from entering the market. Obviously, quality failures, including those related to excipient variability, can have serious consequences to the manufacturer in terms of financial and reputational damage. Ultimately, the end user, the patient, is put at risk. 

Substandard drug products reaching the patient can impact safety and efficacy. And even those that are captured and rejected by quality control or those recalled from the market can lead to drug shortages. This, again, impacts the patient. So, with increasing public focus upon the pharmaceutical industry and regulators alike, it is clear that managing excipient variability will be an area of increasing industry importance. 

It is critical, therefore, for excipient manufacturers and vendors to closely collaborate with the developer to better reduce the risks of quality failures. This is important from early on in the drug product's development, whereby knowledge and experience of the excipient can proactively support robust formulation design and efficient manufacturing control. Failure to account for normal excipient variability can lead to the design and development of nonrobust formulations. Unfortunately, this can necessitate tighter excipient-specification test limits, batch selection, or even custom manufacture to control the performance of the finished drug product. 

It must be recognized that, in some instances, the ability of the excipient manufacturer to meet such requirements may not be easily achieved, if achievable at all. This, therefore, presents additional risk and cost to the overall product. 

It also is important to consider the interplay of all variables including those of the API and the manufacturing process. The use of risk assessment is helpful to identify those primary variables that may affect the drug product's critical quality attributes. 

So, the ability of the developer to determine the effects and interactions of excipient material attributes, along with API and processing parameters, using approaches such as design of experiments, can provide valuable insight into their true criticality upon drug-product quality. 

Using QbD, therefore, presents an opportunity to ensure quality is built in by design. Early collaboration by all stakeholders can better ensure that the potential risks of normal excipient variability can be efficiently designed out by our prior knowledge and available tools. 

 Can you elaborate on that knowledge and related tools and solutions.  

 As I mentioned previously, formulation design is critical to ensuring robust product performance. And to illustrate this point, I would really like to show an example of how normal excipient variability of a rate-controlling polymer, hypromellose (METHOCEL K15M CR) was determined for drug release from a hydrophilic extended-release matrix. The study examined the importance of METHOCEL concentration in regard to managing variation of particle size, viscosity, and percent hydroxylpropoxyl (HP) substitution or percent HP material attributes. And the ranges studied were at the extremes and center point of the cell-specification limits. 

So using propranolol hydrochloride as the model drug, it could be seen that drug release was slower when one increased the METHOCEL concentration from 15% to 30% (w/w), and this, of course, may be expected. The drug release was generally consistent across the extremes of viscosity and percent hydroxylpropoxyl irrespective of drug concentration. Therefore, the formulation was robust to the normal variation of these two material attributes. 

Interestingly, however, for particle size it was clearly shown that lower METHOCEL concentration, 15% (w/w) resulted not only in a difference of release rate, as seen previously, but also increased tablet variability. Here, faster and more variable drug release was shown for the formulation containing the core subparticles of METHOCEL K15M CR polymer. At 30% METHOCEL concentration, however, this variation was not observed. So robust dissolution performance was shown irrespective of the particle size. 

These examples show that it is prudent to determine if such material attributes are a potential risk to drug-product quality attributes during early formulation development.  Clearly, in this stage, it is generally easier to adjust the formulation and/or the process to manage such effects rather than implementation of changes during the latter stages of drug product development. 

The impact of normal excipient variability, however, can also be managed in other ways. Certainly, QbD supports approaches to develop formulation flexibility or formulation design space. Adjustment of the quantitative composition of the drug-product batch can be justified to manage the variability of the ingoing excipient material attribute. As discussed in ICH guidelines, enhanced knowledge of material attributes is needed to develop and justify such an approach.  Nevertheless, it does provide an opportunity for both the developer and the excipient vendor to further collaborate and ensure that the necessary physicochemical properties of the excipient can be evaluated to develop such approaches. 

Furthermore, it also is important not to view the excipient sales specification as the endpoint for control of excipient variation. Excipient sales specifications and test limits can, of course, be variable. Therefore, these may not be representative of the excipient manufacturer's control capability. And I think this is an important point, particularly for risk assessment. Enhanced knowledge here can reduce the perceived risk of excipient property variability upon the drug-product quality attributes. And, indeed, excipient manufacturers may be able to provide prior knowledge of their capability, for example, demonstration of process capability, representative material-attribute trend data, or even descriptive statistics illustrating the control for the individual manufacturing approach. 

In the propranolol matrix case study, another tool available to the developer is that of the excipient material attribute sample. These may be available to assist the developer in proactively testing the effect of normal excipient variability upon its particular formulation. It may not always, however, be useful to study all of the excipient material attributes, particularly if the manufacturer's control is tight and if variability lot-to-lot is insignificant. Such approaches, however, may be valuable to support experimental design and subsequent development of design space. 

Factors for assessing excipient variability, the associated challenges developers need to address to design and manufacture solid oral drug products, and solutions for such challenges are examined.

Quality by Design in Excipients

Efficient and controlled information exchange among excipient manufacturers, distributors, and excipient users is crucial to ensure that the optimal information is obained by the user to better control the drug product. The author discusses the use of various documents and guides by the International Pharmaceutical Excipients Council to facilitate this information flow. 

 indicating that oils, glycerin, and proteins commonly used in the production of human and animal food, medical products, cosmetics, and other FDA-regulated products may contain toxins if they are derived from the 

 plant (1). A common response to this type of notification is for pharmaceutical manufacturers (i.e., excipient users) to inundate their excipient suppliers with questionnaires requesting information regarding raw-material sourcing of their excipients regardless of the excipient purchased or its origin. This approach rarely results in a successful exchange of key information and will many times slow the flow of crucial information to companies that need this information to provide to regulators and other interested parties. 

A more proactive approach would be to adopt the standardized excipient-information approaches afforded by documents provided by the International Pharmaceutical Excipients Council (IPEC). By using these documents, excipient users have information about excipient raw-material sources and other information needed to answer regulators' questions without the need to ask further questions of their suppliers. Instead of reacting to a regulatory or industry news headline by sending out questionnaires pertaining to a supplier's source and method of manufacture of an excipient, a pharmaceutical manufacturer can take a more beneficial and economical approach by first reviewing existing information already available from its supplier. These approaches are explained in IPEC guides, including among others: the 

IPEC Excipient Information Package (EIP) Template and User Guide

 IPEC Quality Agreement Guide and Template

, which offers GMP appropriate for the manufacture of excipients and is a joint initiative between IPEC and the Pharmaceutical Quality Group (PQG).  

A recent example potentially concerning excipients was the use of "gutter oil" to manufacture antibiotic APIs. Gutter oil is a term used in China to describe illicit cooking oil, which has been recycled from waste oil collected from various sources, such as restaurant fryers, drains, grease traps, and slaughterhouse waste. The potential health effects of gutter oil are unclear because experts have expressed opposing opinions on the safety of the intermediate produced using this oil. The topic, however,  became a source of questions from pharmaceutical manufacturers to their excipient suppliers regarding the security of the supply chain of excipients sold in the United States, irrespective of whether or not the excipient could be derived from this material. This incident is another example of where a standardized excipient information package could be used to obviate the need for customer questionnaires and improve the flow of information between excipient manufacturers and users. 

Pharmaceutical companies' understanding of the source, quality, and performance of the excipients they use in their drug products is crucial to ensure the safety, quality, and efficacy of the medicines they produce. Excipients have a wide range of applications and are essential components of the drug-product formulation. Characteristics that excipients bring to formulated drug products include appearance, manufacturability, stability, and delivery of the active ingredient. Understanding their composition, performance attributes, manufacturing, and supply chain is essential. 

Pharmaceutical users should refer to excipient information previously provided from their suppliers during the user's supplier-qualification processes, such as through the EIP. In the 

 and "gutter oil" examples, pharmaceutical companies would have been able to quickly identify excipients that were not subject to the alert and that needed no further follow-up. The informed pharmaceutical user could focus their efforts on the few relevant excipients and APIs. 

The pitfalls of questionnaires and surveys

Regulatory bodies make no statements regarding any regulatory requirements for suppliers to respond to questionnaires and surveys for their customers. Additionally, many excipient suppliers sell only a small amount of their products into the pharmaceutical market and may have little interest in supplying any type of nonstandardized information to pharmaceutical users. Excipient users typically send detailed questionnaires and surveys to obtain information using their own individual formats, which makes answering these questionnaires difficult for the excipient manufacturer.    

The excipient supplier must carefully read each user inquiry to try to interpret the intent of the user's question,  which may or may not relate to the supplier's specific excipient. This situation is obviously more difficult when a language barrier exists. Completion of questionnaires and surveys is time-consuming due to their length and complexity as well as the numbers received by the supplier in all different formats. Furthermore, because these surveys and questionnaires are specific to a particular user, it is impossible for the excipient supplier to identify which responses to inquiries are affected by a change in their operations, and therefore, which customer to alert to the change. Significant resources are expended, both by the user and supplier, to send, complete, return, review, and track these questionnaires and surveys. Finally, for each instance, these responses are a one-time activity and would rarely be updated by a supplier when something changes because these are not the supplier's own documents. 

 for such information provides not only a document controlled by the excipient manufacturer but also ensures that the pharmaceutical customer will be provided with each revision. The nature of the 

, as a dynamic, controlled document with a revision history that is continually updated to address new issues as they arise, supports and benefits both suppliers and users. The 

 allows both parties to have the most current document from which to make assessments of their excipients. Changes to the 

result in a formal revision and notification to the customer.  

 is to provide a standard template for the exchange of information between excipient suppliers and users to simplify the process of information exchange. By responding to surveys, questionnaires, and other requests for information using the standard format outlined in the 

, excipient suppliers can respond in a timely and efficient manner to all such information requests as well as ensure that consistent information is provided and revisions are tracked. The most appropriate course of action when an emerging issue arises should include notifying IPEC-Americas so that the 

Excipient users will be able to anticipate the type and format of the standard data packages they receive from their excipient suppliers when using the EIP. This approach will assist users and suppliers in the management of such information. In the future, electronic transmission of such data packages for direct download may be possible. Additionally, such standardization will facilitate the necessary change notifications pertaining to previously supplied information, thereby further strengthening the excipient suppliers' change-notification program and the excipient user's knowledge and understanding of their excipients and the sources of the excipients.  

 covers specific topics. The minimum information that should be covered in each section are defined; however, additional related information also can be provided at the discretion of the excipient supplier. If particular topics are not applicable to a particular excipient or site, it is indicated in the document. Where information is considered confidential, the document reflects how the excipient user can obtain this information. For example, the document may state that particular information may only be obtained under a confidentiality agreement.  

s do not require signatures (similar to material safety-data sheets, which also are not expected to be signed) as signatures do not add value or authenticity; however, they must be an official company document. Alternatively, a supplier may create a document that provides comprehensive details and explanations rather than immediately updating an 

. The provision of the necessary information by the supplier by means of the

 is more efficient than filling out specific individual customer questionnaires and surveys and the 

usually has better, more complete information.   

The presentation and format of the information is at the discretion of the supplier. Short, bulleted formats are encouraged. Specific phrasing is not prescribed, but suggested phrasing is provided in some sections and can be used if desired. Job titles are used rather than names.   

 documents are version-controlled by the excipient supplier. Suppliers should have a process, in association with their management of change policy, for updating EIP documents in a timely manner, including updates to company and product information, 

 template revisions,  and notification to customers. The current version of the 

can be found on the regional IPEC websites (see, 

http://ipecamericas.org/content/download-ipec-guidance-documents-here

documents are intended to provide useful information to individuals experienced and competent in the area of evaluating excipient suppliers and are not to be viewed as a replacement for audits. They may serve as pre-audit information to help prepare for a supplier audit so that the auditor's time at the site can be most effective. Although the documents are intended to form a complete package of information, each document within the 

was designed as a stand-alone document. Some basic information, therefore, may be common among the documents.  

To provide additional guidance on specific topics, IPEC–Americas maintains a 

lists links to the specific regulatory references applicable in different regions to various sections in the 

 documents. These references provide preparers of 

documents detailed guidance on the information that needs to be included in the various sections. IPEC–Americas' 

is accessible through the IPEC–Americas website (

Provisions of standardized excipient information 

Because not all products are sent from the manufacturer directly to the end user, it is beneficial for a user to create distributors' quality agreements when buying from distributors. Similar principles apply for distributors and manufacturers with regard to information sharing. It is imperative that the distributor has similar agreements with its excipient manufacturers, particularly with regard to change notification. 

IPEC recommends the use of its guides (e.g, 

) for users to obtain information about the excipient distributor, manufacturer, and the excipient itself. The 

is one of the best tools for sharing information using a standard format as it allows excipient suppliers to respond in a timely and efficient manner to all requests as well as ensure that consistent and up-to-date information is provided. 

 explains the standardized excipients information package and is available at 

. It is divided into the following sections:  

: The product regulatory datasheet includes information that the maker and/or supplier provides regarding the product in general, manufacturing, the packaging release site, supplier information, physicochemical information, regulatory information, revision control, and contact information. This section would contain animal origin and raw-material sourcing information.

: The site-quality overview includes the site overview information, compliance evidence, IPEC–PQG GMP compliance details, and miscellaneous site details.

: Supply-chain security information includes the scope of the supply chain, details on  supply-chain security, and specific security information while the excipient is within the supplier's control, subject to agreements with, for example, the distributor,  and safety and environmental information.

IPEC–Americas encourages excipient suppliers to prepare and keep 

 up to date for their excipients and to react proactively when alerts are issued for the latest concern or perceived threat. By updating their 

 and re-issuing them to their customers, much additional work is avoided by all parties, and patient safety is better ensured. 

IPEC–Americas encourages excipient users to use information provided in the 

 format to obtain reliable details regarding the excipients they buy and their related supply chains by supporting the use of a standardized format that facilitates open communication in a more efficient manner. Excipient users should always ask their suppliers if they can provide them with an 

 document rather than requesting that suppliers fill out a questionnaire. Only if the excipient supplier declines to supply an 

 should the excipient user send a questionnaire. By adopting such an approach, the entire paradigm for information exchange between excipient makers, distributors, and excipient users will change and become much more productive for all parties while ensuring that the best information is obtained by the user to be able to better control their drug product and ensure patient safety.  

Notification to Industry: Products Using Oils, Glycerin, or Protein That Were Derived from the Jatropha Plant May Have Toxic Effects

 is North American regulatory affairs manager, MM-Q Regulatory Services, Pharm Chemical Solutions, EMD Millipore, member of the International Pharmaceutical Excipients Council (IPEC)–Americas Executive Committee and chair of IPEC–Americas Excipient Qualification Committee, 

The use of various documents and guides by the International Pharmaceutical Excipients Council can facilitate the flow of information among excipient manufacturers, distributors, and users.

Pharmaceutical Technology-03-01-2013

Advancing Polymers for Solubility Enhancement

Continuous Improvement in Tablet Coating and Dry Granulation

Tackling Common Problems in Tableting and Tooling

Quality by Design in Excipients

Standardizing Excipient Information to Achieve Supply-Chain Security

Concerns and Innovations in Tablet Splitting and Scoring

The Ph.Eur. approach to tablet splitting