At the Spring 2011 ExcipientFest/IPEC conference, PharmTech moderated two speakers roundtables’ regarding developing issues in excipient functionality and continuous manufacturing. Audio files are provided below.

Continuous Manufacturing; Challenges of Going Back to the Future


 Continuous manufacturing offers the advantages of a flexible batch size, potential cost savings, reduced or no scale-up activities between R&D and operations, and a smaller equipment carbon footprint. But there are still challenges to resolve, and questions remain as industry moves further into this new manufacturing paradigm. Exactly how to plan for scale up and a lack of state-of-the-art equipment for all processes pose some problems. And regulatory expectations regarding increased levels of process and product understanding needed to justify a continuous process need further clarification. This roundtable, sponsored by ISP, works through some of these issues. 

Francis Godwin, Compliance Officer in the Division of Manufacturing and Product Quality, FDA 

Dr. Stu Porter, Senior Director of Global Pharmaceutical Applications R&D, ISP

    Mark Neidlinger,  Process Engineering Manager at the Pharma Division, GEA Process Engineering 

 Brett Alexander, Senior Scientist in Global Technical Services, AstraZeneca, US

Chris Moreton, head of FinnBrit Consulting and member of USP and IPEC expert committees

 	Moderated by Angie Drakulich, sr. managing editor,

Excipient Functionality and Developing Issues


 As FDA and other regulatory agencies stress the importance of process and product understanding, the functionality and variability of excipients become extremely important. Excipients vary from APIs by their very nature and have unique properties and characteristics that must be identified, understood, and monitored in the drug manufacturing industry. This roundtable, sponsored by BASF, looks at these issues in detail. 

Dr. Cindy Buhse, Director of the Division of Pharmaceutical Analysis, FDA’s Office of Pharmaceutical Science, CDER, FDA

Catherine M. Sheehan, Director of Excipients at the United States Pharmacopeia, in the Department of Standards Development 

Dr. Lawrence Block, Chair of the USP  Excipient Monographs Expert Committee, and a Professor of Pharmaceutics at Duquesne University

Nigel Langley, head of Technical Sales for Pharma Ingredients & Services at BASF

Chris Moreton, head of FinnBrit Consulting and member of USP and IPEC expert committees 

Dr. Stephen W. Hoag, a Professor at the University of Maryland’s Baltimore School of Pharmacy and a member of the USP Counsel of Experts. 

 
 
 Moderated by Angie Drakulich, sr. managing editor,

Articles

Special Feature

Listen to roundtables from the 2011 ExcipientFest/IPEC conference, addressing developing issues in excipient functionality and continuous manufacturing.

Audio: Excipient Functionality and Continuous Manufacturing

Issue PDF

Pharmaceutical Technology, April 2011 Solid Dosage Supplement (PDF)

Excipients play a vital role in drug formulation. Several leading experts share advances in the field. Stuart C. Porter, PhD, senior director, film coating systems and excipients of global pharmaceutical applications, research and development (R&D), at ISP, provides an overview of solid dispersions as a strategy to improve solubility. Firouz Asgarzadeh, PhD, senior technical manager at Evonik, explains the use of predictive systems in pharmaceutical melt extrusion. Phil Butler, technical sales manager, coatings of pharma ingredients and services at BASF,  examines film coatings for taste-masking and moisture-protection applications. Jennifer Trevor, PhD, senior business development manager, Ferro Pfanstiehl Laboratories, explores uses of pharmaceutical sugars. 

Stuart C. Porter, senior director, film coating systems and excipients, global pharmaceutical applications R&D at ISP

It has been estimated that 40–60% of drugs in development have poor bioavailability due to low aqueous solubility, and this is likely to increase in the future with the increased use of combinatorial chemistry in drug discovery targeting lipophilic receptors. Poor bioavailability results in increased development times, decreased efficacy, and increased inter- and intra-patient variability. Thus, improving drug solubility and, hence, bioavailability through formulation and process technology is a formulator's challenge. 

Several approaches can be considered for increasing active pharmaceutical ingredient (API) solubility in the gastrointestinal tract (GI), including: particle-size reduction, salt formation, nanoparticles, liquid-filled capsules, conventional formulation techniques with surfactants and/or antinucleating agents, and solid dispersions. The use of solid dispersions/solid solutions in pharmaceutical applications to enhance oral bioavailability was first envisioned in 1961. Only recently, with an increasing number of poorly soluble APIs in development, has interest in using solid dispersions in oral dosage forms gained momentum. 

Solid dispersions are molecular (thermodynamically stable solid solutions) and/or colloidal (kinetically stable solid suspensions) dispersions of the amorphous API dispersed in a polymeric matrix. As a result of their morphology and thermodynamic and thermomechanical properties, solid dispersions increase drug surface area, reduce drug crystallinity, and stabilize the system during storage and subsequent administration, 

, to inhibit drug recrystallization. Solid dispersions are most practically and most commonly produced in the laboratory through commercial scales 

either melt-extrusion or solvent spray-drying process technologies. Each technology for forming a solid dispersion has its advantages and limitations.  It has been demonstrated that APIs can be formulated with polymers, such as povidone (e.g., Plasdone, ISP) and copovidone (e.g., Plasdone  S-630, ISP) to provide stable solid-dispersions system with excellent shelf-life stability and dramatically enhanced API solubility and bioavailability, 

Solubility enhancement, however, does not end with the creation of a suitable solid dispersion of the API. Such a solid dispersion has to be successfully incorporated into the final dosage form. If, for example, the final dosage form is a tablet, the physical stability of the API (in solid dispersion form) has to be maintained throughout the shelf life of that dosage form as well as after ingestion up to the point of drug absorption. Many polymers that are used to create solid dispersions are hydrophilic, and so exposure of the dosage form to environmental moisture can compromise the physical stability of the API, with the result that recrystallization may occur on storage. If the tablet releases the API too quickly on ingestion, especially when drug absorption might be a rate-limiting step, the API may recrystallize in the lumen of the gut before absorption can occur. One remedy, for example, if the API is rapidly released in the stomach, but is not absorbed until after entering the small intestine, may be to delay the release of the API in the stomach with an enteric film coating. 

Finally, many oral dosage forms, especially tablets, are likely to be film coated. Because aqueous film coating is the preferred approach today in the global pharmaceutical industry, use of such a process, by potentially adding moisture to the tablet, can again compromise the physical stability of the final product. To mitigate against this risk, one could either employ a non-aqueous coating process (not preferred today) or use a high-solids film coating system (e.g., Advantia Preferred HS Coatings, ISP).  By allowing better thermodynamic control of the coating process, the system prevents moisture from penetrating into the tablet core during film coating. Further enhancements could also be achieved by employing a film-coating formulation that exhibits certain moisture-barrier properties. 

Solid dispersions (overview) section references

Solid dispersion formulation development using predictive approaches Firouz Asgarzadeh, PhD, senior techical manager at Evonik 

Solid dispersion formulations offer effective solutions to the problem of the growing number of poorly soluble drugs (i.e., Biopharmaceutics Classification Scheme (BCS) Class II and IV) in the current pharmaceutical company pipelines. Crystalline drug molecules are converted and stabilized in the amorphous state by the polymeric matrix. Depending upon polymer–drug miscibility, the final product is either a single-phase solid solution with molecular level mixing of the drug molecule or a multiphase matrix containing dispersions of fine particles of crystalline drug within the polymer matrix or a combination thereof. To achieve stable, single-phase solid solutions, selection of polymer–drug combinations with high affinity and appropriate drug-loadings (below saturation concentration) are essential in successful formulation development. Empirical and/or systematic approaches are applied to help with this selection. 

. Empirical trial-and-error methodologies have extensively been used to identify polymer–drug pairs and saturation concentrations in solid-dispersion formulation development. In the empirical approach, binary or ternary blends of drug and polymers, possibly in combination with solublizers, are mixed at several drug loadings. Blends are transformed into solid dispersions 

solvent techniques (e.g., film casting, spray-drying, coprecipitation, and freeze-drying) or heating techniques (e.g., comelting, modulated differenetial scanning calorimetry (mDSC), and extrusion). Finally, these prototype formulations are analyzed for stability and amorphous structure content using physicochemical methods (X-ray diffraction, DSC, atomic force microscopy, Raman specroscopy, Fourier transform infrared spectroscopy, nuclear magnetic resonance, assay/degradation products, and/or dissolution). In the second stage of product development, promising formulations are put on accelerated stability to further refine the selection. Considering the number of available polymers for solid–solution preparation and unknown saturation drug loadings for each drug and polymer combinations, numerous empirical trials are needed to identify appropriate concentrations and miscible polymer–drug pairs. Depending upon available drug supplies and resources, such empirical approaches may not be acceptable due to the cost and too long development-time requirements. 

To reduce the development cost and to accelerate empirical screening time, high throughput screening (HTS) tools, such as 96-well plate formats with in-tube film casting coupled with in-tube dissolution testing have been developed. These tools can screen hundreds of formulations in a matter of a few weeks. Of course, these HTS tools address the time constraint with empirical approaches. However, to select appropriate combinations, an in-depth understanding of structure–properties relations for drug and polymeric matrix is essential through systematic approaches.  

. Systematic approaches to formulation development of solid dispersions can potentially reduce the number of experiments significantly. In such methods, rather than relying on random mixing of drug and polymers, the initial formulations in the screening studies are selected based upon drug–polymer physicochemical properties, such as solubility parameters, hydrogen bonding, and thermal indicators (e.g., glass-transition or melting temperatures). 

One is MemFis (Melt Extrusion Modeling and Formulation Information System, Evonik Pharma Polymers). The system allows pharmaceutical formulators systematic screening of formulations and processing conditions at early stages of solid-dispersion product development to save material and development costs. As the name implies, MemFis has two parts. Formulation Information System uses well- established polymer and organic chemistry group contribution theories to estimate Hansen solubility parameters of drug molecules and polymers. In MemFis calculations, more than 50 chemical group contributions and effects of polar forces (e.g., dipole moments) as well as 40 different hydrogen-bonds on solubility parameters are considered. 

MemFis uses the classical Flory-Huggins equation to identify volume fractions of drug–polymer binary mixtures that would minimize the Gibbs free energy of mixing (i.e.,  saturation solubility limit). 

 = Chi parameter, energy to disperse molecules of polymer and drug; R = gas constant; and T = absolute temperature. 

MemFis can help in reducing the number of experiments by identifying the pairs of polymer and drug that are potentially miscible and have intrinsically better stability 

Melt Extrusion Modeling is a process database that contains more than 1300 experiments collected over a decade of pharmaceutical melt extrusion at Evonik. Once lead formulations are selected from the screening studies, the formulation scientists face the challenge of selecting processing conditions for successful melt-extrusion experiments. Process-setting variables are included, but not limited to extruder screw-element design, heating-zone temperatures, energy-input rate, screw speeds, feed rates, and processing-aide selections. The MemFis process database is expanding and is fully searchable and can provide help with initial melt-extrusion process settings. 

 Naproxen, a BCS II drug substance, was selected for miscibility estimation using MemFis. Film casting from ethanol solutions and cross-polarized optical microscopy was used to measure the experimental drug-substance solubility in the polymers. Estimated predictions from MemFis calculations and experimentally determined results from film casting are presented in Table I.  

Table I: Predictions from MemFis calculations and experimental results from film castings. 

These results show that MemFis predictions were reasonably consistent with experimental measurements. The slight underestimation of solubility in Eudragit E PO is likely due to the ionic interactions between the drug and the polymer, which are not considered in the calculation model. The overestimations for a few of the polymers are most likely due to the fact that such polymers could engage in intramolecular hydrogen bonding rather than intermolecular bonding with the drug and that not all hydrogen-bonding sites on the polymer backbone are available to interact with the drug. 

MemFis predictions help in reducing the number of experiments by identifying polymer–drug formulations with higher potential for miscibility and stability through hydrogen bonding formation. The calculations, therefore, can be used to screen many compounds for miscibility and solid-solution formation minimizing API use and development time. 

Solid dispersion (predictive approaches) section references

Jennifer Trevor, PhD, senior business development manager, Ferro Pfanstiehl Laboratories

The International Pharmaceutical Excipients Council (IPEC) provides 13 broad categories of excipients for solid dosage forms based upon function: binders, disintegrants, fillers, lubricants, glidants, compression aids, colors, sweeteners, preservatives, suspending/dispering agents, film-formers/coatings, flavors, and printing inks. Key features of excipients used in solid dosage manufacturing have traditionally been based upon flowability and particle size, among other characteristics. 

One factor to consider when choosing an excipient is the desired release characteristics, whether it be immediate, sustained, or modified release (1). Quick-dissolving tablets have garnered more attention of late, especially with regard to using trehalose, a disaccharide of glucose, in solid-dosage formulation (2). One important feature that make this an attractive excipient for this usage is that it does not absorb water readily in the crystalline state, which lends to enhanced stability and reduced stickiness (3). Ohtake et al. recently wrote an extensive review article on the unique usages of trehalose in solid dosage forms. The authors noted that the information on trehalose-containing pharmaceuticals in the US is limited; however, there are a number of patents claiming the use of trehalose in solid-dosage applications. 

Another attractive attribute of trehalose is the avoidance of Schiff bases from the reaction of aldehydic sugars with primary and secondary amines, such as what occurs with lactose. Trehalose does not react with amino groups and therefore is an attractive choice as a bulking agent. Additionally, anhydrous trehalose is not subject to undue hardness, such as lactose, and dissolves readily. Thus, the potential for developing trehalose in solid-dosage formulations is expanding.  

 , DOI: 10.1002/jps.22458, Feb. 18, 2011.  

Film coatings in taste-masking and moisture protection

Phil Butler, technical sales manager, coatings of pharma ingredients and services at BASF

Coating of solid oral dosage forms is an effective and economical route to providing moisture protection and taste-masking properties to moisture sensitive and bitter- tasting active ingredients (1). To achieve both properties using the same polymer, chemical functionality needs to be designed to provide not only insolubility in saliva (pH 6.8–7.2) for protection from unpleasant taste, but also reduced affinity to water for moisture protection. 

Methyl methacrylate and diethylaminoethyl methacrylate copolymer dispersion (Kollicoat Smartseal 30 D, BASF SE) provides this dual functionality along with a fast release of active ingredients in the stomach (see Figure 1). The diethylaminoethyl basic functional groups result in an insoluble polymer at basic and neutral pH values and a quick-dissolving polymer at pH values below 5.5 (2).

Figure 1:  Solubility of methyl methacrylate and diethylaminoethyl methacrylate copolymer dispersion. 

The performance as a taste-masking agent was evaluated by a human-taste panel. This assessment correlates very well with results from 

dissolution tests at pH 6.8 (see Figure 2), which proved to be a reasonable substitute and therefore suitable for quality-control purposes. The results in Figure 3 demonstrate that coating levels of 4–5 mg/cm

  of a Kollicoat Smartseal 30 D based formulation can effectively mask the unpleasant taste of quinine hydrochloride tablets.

Figure 2: Quinine hydrochloride dissolution in ph 6.8 phosphate buffer. 

A robust film-coating formulation is needed in the compression of coated particles into tablets as with taste-masking of pediatric, chewable acetaminophen tablets. Maintaining coating integrity and eliminating particle-coating failure are important for intact coating functionality after compression. To determine optimal use level for similar applications with methyl methacrylate and diethylaminoethyl methacrylate copolymer dispersions, cast films were plasticized with tributyl citrate, triethyl citrate, and acetyltriethyl citrate at levels between 10 and 25% for elongation at break comparison. Elongation at break values of approximately 100% were attained using 13–15% plasticizer content range, which provides sufficient flexibility for coated particle compression applications (3).

Featured Content

This technical forum is part of a special issue on Solid Dosage and Excipients.

Exploring Excipient Functionality

Many pharmaceuticals are produced in premetered doses: as tablets, for example, or as powders for inhalation or for dissolution before intravenous or oral delivery. Filling processes into tablet dies, capsules, and other vessels, are therefore a routine aspect of pharmaceutical manufacture. The goal of these processes is to ensure the consistent and precise extraction of the required dose at an acceptable processing speed.  

Filling machines may have complex and varied designs and geometries, depending on the application for which they are used, and on the properties of the process material. Oral capsules, for example, typically have a fill weight in the range of 50 to 500 mg, while dry-powder inhaler (DPI) applications require a much smaller mass, usually between 0.5 and 15 mg, and tend to involve highly cohesive formulations. The optimal filling procedure is different in each case, but well-controlled, uninterrupted powder flow through the selected geometries is a prerequisite for efficient processing. Success is judged by the consistency of the fill weight. 

Identifying a suitable filling solution for a given formulation at the outset minimizes operability problems over the long term. Relevant characterization of the formulation (i.e., measuring the properties that predict how it will behave during processing) is the first step. This principle is especially true in the context of recent regulatory initiatives, such as quality by design, which emphasize a thorough understanding of the process-control space. To select the best filling geometry and properly control manufacture, it is necessary to measure the powder in a way that reveals how it will perform as it flows through the filling machine.  

This article details a recent experimental study by Freeman Technology and Innovative Technology for Custom Machinery (ITCM) to explore correlations between powder properties and behavior in two filling geometries. The results confirmed that no one-size-fits-all filling solution exists, but pinpointed the properties that can be usefully measured to achieve a compatible powder–plant match in filling applications. 

Different geometries for different formulations

A recent study evaluated the performance of four pharmaceutical excipients (i.e., S1, S2, S3, and S4) for two filling configurations using a commercially available dosing and filling machine. Figure 1 shows configurations A and B. In both configurations, powder flows down through a channel to a pocket on a rotating wheel. As the wheel rotates, powder is transferred from the pocket to a waiting receptacle, and the wheel rotates back to the filling position. 

 Figure 1: Filling geometry configuration A (left) and filling geometry configuration B (right).			

The volume of the pocket into which powder flows is the same (~410 mm

 ) in both geometries. On the other hand, with configuration A, the feed channel is narrower and more closely matched with the diameter of the pocket opening. In contrast, the feed channel in configuration B is much wider, encircling the entrance to the pocket. 

In both systems, the extraction of a consistent volume relies on the complete filling of the pocket every time the wheel rotates, and on the efficient transfer of that volume to the waiting receptacle. Consistent volume translates directly into consistent mass, which is the goal of the process, as long as bulk density remains the same. Process performance for each of the excipients was therefore described using a process-capability index, C

, derived from the weight variance of the doses produced (1).  

To fully characterize the properties of each of the four formulations, personnel subjected them to multifunctional testing using a powder rheometer. During the past decade, powder rheometers have evolved to offer multiple measuring techniques in a single instrument, including shear, bulk, dynamic, and axial methods. Personnel measured shear, bulk, and dynamic properties to quantify properties, such as cohesiveness, flow function, aeration ratio, basic flow energy, and permeability. 

Cohesion and flow function are parameters derived from shear-test data. With this methodology, one powder face is sheared against another to ascertain the strength of particle interactions. Shear testing is a well-established, widely recognized technique, but has the limitation that powders are measured in a consolidated state. Information about how the powders will behave when flowing freely or when aerated is derived theoretically rather than measured directly. High flow functions typically are associated with powders with low cohesion that are expected to flow freely, whereas low flow functions assume high cohesion. 

Dynamic testing is a modern technique that involves measuring the forces acting on a blade as it rotates along a defined path through the powder sample. These measurements are used to determine the energy required to induce flow. The powder is measured in motion, hence the term "dynamic." This technique enables the testing of consolidated, conditioned, aerated, and fluidized powders. Aeration ratio, for example, is a parameter that indicates the extent to which flow energy changes when the sample is aerated. Generally speaking, the flow energy of cohesive materials changes little when the sample is aerated. The attractive forces between particles resist particle separation, and the air channels through the powder bed, having relatively little effect. In contrast, with less cohesive materials, the air flows between the particles, substantially facilitating movement within the bed and dramatically reducing flow energy. Aeration is therefore a complementary way of investigating cohesiveness in a way that arguably reflects in-process behavior more closely than shear testing alone. Reference 2 provides a more complete description of all of the powder testing techniques used in this study. 

Correlating process performance with powder properties

Figures 2 and 3 show correlations between filling performance and four powder properties for configurations A and B. Data are shown for all four formulations for configuration A, and for S1, S2, and S4 for configuration B. S3 was not intended to be processed on configuration B during production, and data for this combination are therefore unavailable.

 Figure 2: Correlations between filling-performance Cpk in configuration A and various powder properties.			

The results indicated that for configuration A, less cohesive materials were more compatible than cohesive materials. High basic flowability energy, aeration ratio, and flow function, along with low cohesion, were correlated to improved processing performance. All of these features indicated low cohesiveness. The findings suggested that for this configuration, the powder's ability to flow freely into the feed channel and pocket determined process performance. The small feed diameter of the configuration made this design more susceptible to the powder arching and to the discontinuous flow that can occur with cohesive materials, which could have a dramatic effect on processing performance.

 Figure 3: Correlations between filling performance Cpk in configuration B and various powder properties.			

The results for configuration B showed different behavior. For this configuration, cohesive formulations (i.e., those with low basic flowability energy, aeration ratio, and flow function) performed better. This suggested that with the wider feed channel, the ability of the powder to flow freely under gravity was less important. Further research would be required to fully understand the mechanisms that gave rise to the observed behavior, but it is worth reiterating that the filling process involves more than simply filling the pocket. Successful transfer of the extracted volume as the wheel rotates is also essential. The wide feed channel may have encouraged successful pocket filling for all formulations, regardless of cohesiveness, but as the wheel rotates, less cohesive materials may have been lost more easily, thus compromising dose weight. The types of powders that were optimal for configuration A clearly were suboptimal for configuration B, and 

To succeed in matching filling-machine geometry to the demands of a specific formulation, it is critical to gain a good understanding of the relationships between powder characteristics and process performance. The results presented in this article suggest that the optimal powder property set depends on machine geometry. Although free-flowing formulations are preferable for certain geometries, as might be expected, cohesive formulations perform better for other geometries. 

The data indicated that certain types of geometry were better suited to cohesive materials, thus highlighting the importance of studies such as these for personnel who develop filling solutions. Equally important, the data suggested that new, free-flowing formulations will not necessarily perform better on an existing unit than previous products. Appropriate powder testing holds the key to achieving a compatible powder–geometry match that delivers efficient operation over the long term. 

 is director of operations at Freeman Technology, Boulters Farm Centre, Castlemorton Common, Welland, Worcestershire, WR13 6LE, UK, tel. +44 0 1684 310860, fax +44 0 1684 310236, 

The author explains how to gain an understanding of the relationships between powder characteristics and process performance to match filling-machine geometry to the demands of specific formulations.

Correlating Die-Filling Performance with Powder Properties

Excipients are used in almost all approved drug products in some way and are essential to the performance of the product. Most excipients used in pharmaceutical products are manufactured to comply with pharmacopeial standards and are used in multiple products. Excipients vary from active pharmaceutical ingredients (APIs) because they are used in many drug products and have different functional characteristics depending on the particular formulation. 

Current IPEC guidelines and excipient controls

The International Pharmaceutical Excipients Council of the Americas (IPEC-Americas) is an organization representing makers, distributors, and users of pharmaceutical excipients. IPEC–Americas is a member of the recently established IPEC Federation. The federation was formed in 2010 to coordinate IPEC's global activities in the areas of compendial harmonization, excipient guideline/standard development, and coordination of excipient supply-chain security initiatives with regulatory agencies throughout the world. The federation's current membership is made up of IPEC–Americas, IPEC–Europe, IPEC–Japan, and IPEC China.  

IPEC–Americas has also formed two partnerships in Latin America to allow that region's growing pharmaceutical and excipient industry to participate in IPEC activities. The partnerships also allow the Latin American pharma and excipient industry to use IPEC guidelines to improve drug quality and protect patients. 

 IPEC has developed guidelines, programs, and proposals on various aspects of excipient control during the past 20 years. Each guideline fills a specific need related to an area of excipient control (see Table I). These guidelines and whitepapers have been used by many companies and regulators to establish appropriate standards for excipient control throughout the world. 

 Table I: IPEC Excipient guidelines and whitepapers available on ipecamericas.org.			

IPEC's efforts to assist the Pharamcopeial Discussion Group (PDG) with monograph harmonization has also helped to establish scientifically justified test methods and specifications for pharmacopeial excipients that can be used globally. Many IPEC proposals have resulted in providing the key excipient information and expertise needed to modernize and harmonize existing monographs in the 

United States Pharmacopeia–National Formulary (USP–NF)

IPEC developed an Excipient Safety Guideline (FDA participated on the committee as an advisor) that was published in 1996 in

(1) to provide guidance on how the safety of new excipients should be evaluated. FDA then published its own guidance document in 2005 titled, 

Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients

, which was based on much of the work done to develop the IPEC guideline and is now the standard for how FDA assesses the safety of new excipients when used in a dosage form (2).  

IPEC also recently collaborated with FDA to implement a New Excipient Safety Evaluation Procedure. The procedure provides a mechanism for independently assessing a new excipient for safety and to establish an initial precedence of use (3). 

IPEA third-party auditing and certification

Recognizing the importance of supplier qualification and auditing to improve supply-chain security, IPEC established the International Pharmaceutical Excipients Auditing (IPEA) in 2001 to perform qualified third-party audits of excipient manufacturers for which the audit reports can be shared with user companies throughout industry. In 2010, IPEA went through an intensive ANSI qualification program that resulted in IPEA becoming the first independent, ANSI-accredited organization that can perform qualified third-party audits and certifications of excipient manufacturers and distributors.  

The formation of IPEA and its recent ANSI accreditation represent a major step forward in providing the industry with an alternative for obtaining GMP audit information from suppliers. Some excipient users find that suppliers are not willing to let them perform an audit if they purchase a small amount of the excipient. In other situations, the supplier may not be willing or have the capabilities to host an audit for every customer. That same supplier may, however, be willing to host an IPEA audit or become certified by IPEA as a means of providing qualified GMP audit information to multiple customers at a reduced cost. 

Utilizing the full excipient control toolkit 

In recent years, IPEC worked to pull together its various guidelines to create an Excipient Qualification guideline. The 2008 guideline provides overall guidance on how to use a number of related IPEC guidelines to build a credible excipient qualification program from both the maker's and the user's perspective. 

As IPEC moves into its third decade, the council is taking this concept further to develop a system of Total Excipient Control (TEC). The system will use all existing IPEC guidelines, programs, and proposals to build an overall control system from the time an excipient manufacturer thinks of marketing a chemical as an excipient to the pharmaceutical manufacturing industry's use of that excipient to the time the patient takes the drug product containing the excipient.  

The TEC system involves three areas of control: excipient design, excipient safety, and excipient manufacturing process control and distribution (see Figure 1). Excipient design controls address setting design criteria in a way that meets the perfromance requirements for the intended use. The controls also take into account quality-by-design (QbD) principles. 

Figure 1: Total Excipient Control (TEC) involves control in three main areas to maximize patient safety. QA is quality assurance.			

Ensuring excipient safety involves using information that has been developed to support the safe use of the excipient in the intended application at the levels of use expected to be experienced by the patient. Excipient manufacturing process control and distribution is the area of control traditionally covered by GMPs, auditing, quality-control testing, information-sharing, and supply-chain security. 

As part of developing the TEC process, IPEC has identified some areas that are not fully covered by current IPEC guidelines and programs. The following sections of this article provide some details related to IPEC's plans in this regard.  

 Validation is one of the most commonly misunderstood issues that comes up during pharmaceutical company audits of their supplier's excipient manufacturing facilities. Pharmaceutical company auditors often ask excipient manufacturers for their validation data on the manufacturing or cleaning process and do not always get the information they are looking for because excipient manufacturers do not always have formal validation studies compiled in the manner typical of the pharmaceutical industry. In many cases, the problem is tied to the terminology rather than an actual issue of control.  

Excipient manufacturers typically have a huge amount of process-capability data that is essentially the same type of data that a pharmaceutical company would call "validation data," but it is often stored in sophisticated large-scale computerized process-control systems in a different format from that usually used by the pharmaceutical industry. Sometimes, due to terminology differences during the audit, the excipient company doesn't realize that this information is what the pharmaceutical auditor needs. Process-capability data can, however, provide appropriate excipient control and, in many cases, can provide information far beyond what is typically obtained in pharmaceutical validation studies.   

To address this common misunderstanding, IPEC is drafting an Excipient Validation Guide which will clarify how validation studies should be handled for excipients. This guide will help excipient manufacturers convert their process capability data into useable information that will provide pharmaceutical users with a better understanding of how the excipient processes are controlled. Ideally, this guideline will lead to fewer unnecessary observations during audits of excipient manufacturing operations and help excipient manufacturers better understand what type of validation or process-capability information they should have in place.  

Excipient composition: additives and processing aides.

As noted above, IPEC published an Excipient Composition Guide that provides details about the types of components which are typically part of an excipient's composition and how to go about developing an appropriate excipient composition profile. However, there is still much confusion in the industry and regulatory community related to the presence of additives and residual processing aids. These components have always been part of various excipients' composition but have not been routinely discussed. 

It is crucial in a QbD environment that information concerning the additives and residual processing aids which may be present in an excipient be shared with the users so that adequate developmental work can be done to understand any interactions that may occur between the additive or processing aid and the other components of a drug product. There have been many reports of instances where the presence of a small level of an antioxidant or other additive in an excipient has affected drug-product stability or other performance properties. 

The difficulty for industry lies in how regulators may respond when they find out that an existing excipient has always had an additive or residual processing aid in it and that this information had not been disclosed in the past. Companies are concerned about compendia and regulatory complications if this information is brought out. Therefore, companies are currently struggling to have appropriate discussions concerning the presence of additives and residual processing aids. 

To address this situation, IPEC–Americas is compiling a list of additives and processing aids that are known to be commonly used in a number of excipients. The actual excipients which contain these additives and processing aids are not being identified at this point due to concerns the manufacturers have for confidentiality and unknown regulator reaction. IPEC–Americas plans to submit this list of well-known additives and processing aids (typically GRAS or excipient materials on their own right) to FDA. The organization also will request a meeting with FDA to discuss how best IPEC can work with the agency to find a mechanism (possibly grandfathering) that could be used to provide a way for excipient manufacturers to provide specific additive and processing aid information to FDA in a manner such that the presence of these materials can be considered to be acceptable in specific excipients in the future. Ultimately, this information could then be placed into the 

monographs to show that there is no problem with these materials being present as long as they are identified. In some cases, due to confidentiality, there may need to be disclosure of this information to FDA through the use of a drug master file. 

Once IPEC–Americas discusses this issue with the FDA and determines a process for handling the situation, IPEC will pursue similar discussions with other regulatory agencies globally to try to obtain similar flexibility. It is crucial that these discussions occur because additives and residual processing aids exist in numerous excipients and always will. It is important that global regulators find a way to effectively deal with this issue. The alternative, regulators saying these excipients can no longer be used, for example, would have a significant negative impact on the availability of many drugs. This issue has caused problems in Japan already, and IPEC hopes its efforts to obtain some type of grandfathering of these materials will lead Japanese regulators to make certain changes in its laws and guidelines to allow for these additives and processing aids in excipients. Japanese regulators may also need to determine the appropriate levels of use for particular applications. 

Another hot topic concerning excipient composition is the presence of visible particles (not contaminants) in excipients that may typically exist and how users should deal with their presence. These particles may be off-color, charred particles from heat in the manufacturing process, small amounts of metal particles which typically occur from normal manufacturing process-equipment wear, or other types of particles that are visibly different from the main excipient particles but may be present as a part of the normal process that cannot be easily removed. Typically, these particles have no safety implications. 

IPEC has established a subcommittee of its Composition Committee to develop a guideline on how to determine when the presence of these particles is acceptable depending on their type, number, and size. This guideline will also discuss appropriate testing methodologies for assessing these visible particles and what may be necessary to characterize the particles' identity. 

 The ICH Q3D guideline and the USP general chapters on elemental impurities currently under development will head toward implementation in the next few years. These guidelines and chapters will have a significant impact on the pharmaceutical and excipient industry going forward. Many excipients contain small amounts of elemental impurities and these amounts may cause some drug products to exceed the limits proposed. As a result, some drug products may need to be reformulated. It is the opinion of IPEC that the official implementation timeline of these guidelines and chapters be delayed until appropriate characterization studies can be carried out by excipient manufacturers to fully understand what levels of these elemental impurities may exist in their excipients.  

In the past, excipient users had to perform a heavy-metals limit test. This test did not provide much useful information about the actual impurity levels were in the excipients. IPEC plans to work with the industry to encourage appropriate analytical studies once the ICH Q3D limits are known so that this information can be shared with pharmaceutical users. Pharma-excipient users can then establish the appropriate calculations to determine what levels of elemental impurities may exist in the finished dosage form and whether their drug products comply with the established limits. 

 IPEC has identified and is working on several other excipient-control areas that need further guidance. These include:			

QbD: excipient variability in chemical and physical properties and the effect of this variability on drug product manufacturability and performance 

Coprocessed excipients: supporting analytical data to build safety bridging arguments to component safety data  

Atypical actives: excipients being used as APIs that are not manufactured using ICH Q7 (4). 

There are still many gaps in IPEC-Americas' TEC system. However,  the organization is dedicated to continue to develop appropriate guidelines and whitepapers to fill these gaps and find ways of combining all of IPEC's tools into a workable system of controls that begin with excipient design and ends with patient consumption. If IPEC can do this, patient safety will surely be improved. 

 is vice-chair for Scientific and Regulatory Policy at the International Pharmaceutical Excipients Council of the Americas (IPEC–Americas). He is a member of 

, Guidance for Industry: Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients 

Good Manufacturing Guide for Active Pharmaceutical Ingredients (Geneva. November 2000)

The author focuses on how industry can build a system for Total Excipient Control.

Total Excipient Control: A Pathway to Increased Patient Safety

See a video demonstration at the end of this article

Maximizing physical-chemical identifiers: Colorcon and ARmark's visual and covert film-coating technologies

The regulatory landscape for improving anticounterfeiting technologies has greatly improved in recent years, especially with regard to solid-dosage coatings. According to John D'Ottavio, quality and regulatory affairs manager for ARmark Authentication Technologies, LLC, FDA's 2009 draft guidance on physical–chemical identifiers (PCIDs), 

Incorporation of Physical-Chemical Identifiers into Solid Oral Dosage Form Drug Products for Anticounterfeiting

, opened the door to new security options for the pharmaceutical industry.  

"The majority of anticounterfeiting or authentication approaches used today focus on primary packaging and labeling, and not the product itself," he says. "But the guidance offers specific recommendations regarding the use of inks, pigments, flavors, and other molecular taggants in immediate-release film coatings on solid oral-dosage forms." 

PCIDs offer several benefits to industry. "In the fight against counterfeiting, one of the more interesting breakthroughs in PCID technology can be seen in the development of (R)mark On-Dose ID microtags, a technology created by ARmark Authentication Technologies, LLC and Colorcon, Inc. By leveraging the tablet coating expertise of Colorcon, a world leader in the manufacture and development of specialized film coatings, and ARmark's customized microtag authentication technology, the two companies collaborated to enable greater security by authenticating solid oral dose pharmaceuticals. 

The microtags are embedded with unique information for the purpose of authenticating solid oral-dosage forms, explains D'Ottavio. "The microtags are applied directly to pharmaceutical tablets during the film-coating process for reliable placement on each and every tablet without changing any aspect of the existing film-coating process of an approved product. This flexibility can save ample costs in terms of additional machinery." 

Adds Kamlesh Oza, film-coating general manager at Colorcon, the covert microtags are custom-developed from approved excipient materials listed in FDA's Inactive Ingredient Database (IID). "Their unique physical–chemical characteristic make it possible to authenticate legitimate dosage forms and identify counterfeits under magnification. These markers are invisible to the naked eye," says Oza. 

The microtags function as a unique hidden fingerprint embedded with information specified by the brand owner, explains D'Ottavio. The tags are compatible with other covert or overt identification technologies, and are made to hold significant amounts of information in a space of 75 to 120 µg (i.e., smaller than the diameter of a human hair). "The information included in the microtags is customized to each client and may contain multiple levels of security, such as lot and batch ID numbers, country codes, dates, and logos as well as other text, patterns, shapes, and symbols. These types of forensic-coded signatures offer an additional level of security that makes the technology virtually impossible to replicate," says D'Ottavio.  

ARmark's trademarked (R)vision systems allow for easy identification of the microtags. Simple hand-held optical tools authenticate a product by magnifying the microtags at any stage following the coating process. "The simplicity and portability of the (R)vision system enables accurate, in-field detection within a matter of seconds without destroying the drug sample," says D'Ottavio. "Another major benefit of this system is its interoperability. For example, the system does not require sophisticated external databases, communication networks, or integration into complicated data systems or laboratory sites to authenticate a product. All that is required is a visual confirmation that the microtags are present and contain the correct information." 

According to Colorcon's Oza, the pearlescent pigments in fully-formulated  film coatings are also considered PCIDs under the 2009 FDA draft guidance. Pearlescent coatings, in general, could increase counterfeiting protection because the unique color-shifts across the tablet surface are difficult to duplicate without knowing the specific combination of pigment properties and processing procedures.  

Explains Oza, "A multitude of colors can be achieved using the same chemical entity controlled by various parameters that are difficult to reverse-engineer. Pearlescent coatings are also easily recognized by physicians, pharmacists, and patients as the original manufacturer's product. In this sense, visual identification can be further enhanced by using unique colors, coupled with a tablet's shape and size, or by using printing methods to place unique images and logos on the tablet's surface." 

In terms of regulatory implications, Oza says that the pigments contained in the pearlescent coatings meet current 21 

 colorant regulations. The coatings are custom-developed from approved GRAS ingredients or listed in FDA's IID; produced under cGMP conditions; compatible with existing coating processes; and typically have no impact on dissolution or stability.  

He adds that, "the addition of the microtags or pearlescent pigments to an existing immediate-release film coating would typically be considered a SUPAC Level 1 Change and documented in a company's next annual report. This flexibility can allow for quick incorporation of this technology into drugs which are known or suspected counterfeit targets." 

 Figure 1 (ARmark): Microtags, with unique information specified by the brand owner, can be embedded in a space on a tablet smaller than the diameter of a human hair. Magnified image shows microtags on the surface of a blue film-coated tablet.  

 Covert on-dose microtag technology is also important for addressing growing supply-chain concerns throughout industry because it enables companies to use the information embedded within the microtag to immediately understand a product's traceability. "Not only can the microtags prove authenticity of the solid oral-dosage form, but they can also contain information that sheds light on the distribution practices once a product leaves the manufacturing site," explains ARmark's D'Ottavio.  

"From a track-and-trace perspective, the microtags can provide the technology to distinguish authentic product from adulterated supplies," he says. "But when these tags include information, such as batch or country codes, the drug manufacturer can take a closer look at understanding where the product originated to gain insight as to how the product was handled in the field." 

Looking ahead, Colorcon's Oza comments on what the future of drug-anticounterfeiting technology may hold. "Due to the complexity of today's distribution system, no single anticounterfeiting technology can guarantee full counterfeit protection. However, if a drug product is designed with layers of identification on the dosage itself, and then packaged with a variety of features that are hard to duplicate, counterfeiters may turn their sights elsewhere," he says. "The key is to ensure that a pharmaceutical is made difficult to duplicate. Procuring noncommodity coating options will impart the most security." 

Accelerating tablet shape selection: Pfizer and DEM Solutions' predictive computational model

The following section is provided by William R. Ketterhagen, senior scientist, and Mary T. am Ende, associate research fellow, both with Pfizer Worldwide Research & Development, and by Richard D. LaRoche, vice-president of engineering and US general manager, and Oleh Baran, senior consulting engineer, both with DEM Solutions. The authors discuss a recently developed predictive computational model that can help guide pharmaceutical manufacturers in the selection of tablet shape and operating parameters for a given equipment geometry to ensure film-coating uniformity.

Designing and developing robust drug products can be a costly endeavor, especially when commercial-scale studies must be performed to determine nonscalable or unpredictable process parameters. Even in tablet-film coating, where some aspects, such as the thermodynamic conditions in the pan and spray atomization are relatively well understood, coating uniformity can vary for tablets of different core shapes and different coating-process conditions  (1, 2). In this regard, the coating process is not entirely scalable from laboratory studies due to differences in tablet-mixing in the pan (3). The introduction of a new tablet shape, for example, can result in unexpected variations in the uniformity of film-coating thickness, requiring physical testing that is costly in time, materials, and labor.  

Although some experimental work can be avoided through the use of models, poor coating uniformity often requires experimental trials to determine the operating conditions that produce desired coating results when moving from laboratory to commercial scale (1, 2). As a solution, Pfizer Reseach and Development has developed a predictive computational model using EDEM, discrete element method (DEM) software developed by DEM Solutions. The method has been confirmed experimentally to guide selection of the tablet shape and operating parameters for a given equipment geometry such that uniform film-coating thickness is obtained (4). 

Uniformity of film-coating thickness is an important tablet quality attribute for a number of reasons. Poor uniformity or significant variability in film-coating thickness, can lead to a range of issues, depending on the purpose of the coating. In the case of coatings containing an active pharmaceutical ingredient (API), variability in potency between tablets arises directly from coating variability. For a functional coating governing the drug-release profile, variability in thickness can lead to variable drug-release profiles. Finally, high levels of variability for cosmetic coatings results in longer process times to ensure that all tablets have received a sufficient amount of coating.  

In practice, obtaining uniform coating depends on good mixing of the tablets in the coating pan and a uniform distribution of tablet orientations in the spray zone to ensure uniform exposure of all sides of each tablet to the coating spray. The tablet-flow dynamics are governed by several factors, including the equipment geometry, the presence of any mixing elements (e.g., baffles), the conditions under which the equipment is operated, and the properties of the tablet cores, including size and shape. To fully explore the effects of each of these factors on film-coating uniformity necessitates a large number of physical experiments. Developing a model to study these effects 

 offers great savings in time, material, and labor costs.  

DEM models are capable of accurately reproducing particle behavior in a number of pharmaceutical manufacturing processes and are growing in use throughout the industry (5). During the past few years, Pfizer has developed DEM models of various processes involving solid dosage forms using EDEM, a commercial DEM software package. Previous reports in the literature on film coating uniformity are limited to spherical, standard round convex (SRC), or oval tablet shapes, and are often focused on operating conditions rather than tablet shape (6–8). The computational approach reported here predicts both intertablet (i.e., uniformity between tablets) and intratablet (i.e., uniformity between surfaces of a given tablet) coating uniformity and allows for the study of many tablet shapes, including less common almond or bullet tablet shapes, permitting rapid screening of tablet shapes and operating conditions that ensure quality of tablet coating uniformity. 

To investigate intertablet coating uniformity, EDEM simulations of the operation of pan coaters were carried out at various batch sizes, pan speeds, and different tablet shapes. The results were analyzed to determine the distributions of the residence time per pass through the spray zone for each tablet and the circulation time between successive appearances in the spray zone (see Figure 2). For conditions in which these distributions are wide, poor intertablet coating uniformity usually results. In a laboratory-scale coating pan, simulations predicted that the residence-time and circulation time variability both decrease with faster pan speeds. The effect of pan loading is mixed—residence time variability decreases with increasing loads but circulation time variability increases with increasing loads. The net effect in this case is an increase in variability for larger pan loads. Thus, improved intertablet coating uniformity is expected for faster pan speeds and smaller batch sizes, but consideration must also be given to maintaining reasonable process throughput, and the potential for increased tablet attrition that may occur at fast pan speeds. 

Figure 2  (PfizerâDEM): Simulation image of bullet shaped tablets in a laboratory-scale film coating pan where intertablet coating variability is shown by varying degrees of blue color on each tablet, indicating the total residence time in the spray zone for a given tablet. 

Tablet shape was found to have little effect on intertablet coating uniformity but did, however, play a role in intratablet coating uniformity due to the extent to which tablets have a preferred orientation as they pass through the spray zone. The analysis of several different tablet shapes shows a trend with an orientation index (OI)—a quantitative measure of the existence of a preferred tablet orientation in the spray zone—that correlates with a mean aspect ratio of the tablet shape (see Figure 3). Tablets with a smaller mean aspect ratio tend to have improved intratablet coating uniformity over those with a larger mean aspect ratio.

Figure 3 (PfizerâDEM): The Orientation Index (OI) describing the extent of a preferred orientation in the spray zone- and the resulting likelihood for poor intra-tablet coating uniformity-is shown for several tablet shapes. The mean tablet aspect ratio (A) is defined by the tablet length (L), width (W), and thickness (T).  The dashed line represents the least squares linear fit to the data. 

The deployment of EDEM modeling in Pfizer drug-product development has accelerated the decision-making process by predicting, before process scale-up, the performance of commercial tablet shapes at process scale. The modeling is rapid, broadly applied across the solid-drug product portfolio, and has flexibility to assess unique shape decisions early in the development process.  

The value of this predictive computational tool was estimated using DoOptima software (Decision Options, LLC), which uses a market normalization process to analyze the impact on projects at various phases accounting for the typical number of projects transferring to commercial scale per year, the material, manufacturing, supplies, and labor costs associated with conducting the trial compared with the cost of the software license and resources for the simulations. The net present value of predictive modeling for film-coating scale-up was estimated at approximately $500,000 in the first year (9). Based on this success, the future focus should be to continue to advance and deploy predictive computational models to support drug product development and commercialization. 

See a video demonstration from DEM Solutions

 5. W.R. Ketterhagen, M.T. am Ende,and B.C. Hancock, 

Drug Development and Industrial Pharmacy 

Eur. Jrnl. of Pharmaceutic. and Biopharmaceutic.

 9. M.T. am Ende, B.C. Hancock and K. Huta, "An Approach for Estimating the Value of Computational Tools in Drug Product Development," presented at the AIChE Annual National Meeting, (Salt Lake City, UT, Nov. 10, 2010).  

Representatives from Pfizer R&D, DEM Solutions, Colorcon, and ARmark Authentication Technologies provide insight into recent tablet-coating technologies.

Innovations in Tablet Coating

The primary focus of risk assessment for the use of excipients in any drug product is patient safety. According to the International Conference on Harmonization (ICH) Q9 guideline on quality risk management, "Quality risk management is a process that supports science based and practical decisions when integrated into quality systems" (1).

Twenty years ago, excipient manufacturers, distributors, and users established the International Pharmaceutical Excipients Council of the Americas (IPEC–Americas) to apply the concept of science-based and practical decision-making to the evaluation, qualification, and control of excipients. Since its inception, IPEC has developed and promoted the implementation of appropriate and scientifically valid, voluntary industry guidance documents for the excipient industry.  

IPEC's mission has been and continues to be to ensure that excipients meet the highest appropriate standards for quality, safety, and functionality throughout their manufacturing process and supply chain. The use of risk-management principles furthers this cause. 

In a recent article, J. Orloff aptly noted "the potential for quality risk-management to degenerate into a non-value added exercise of identifying noncritical, improbable, low-risk scenarios indefinitely" (2). Equally detrimental to effective application of risk-management principles is the blinding self-deception emerging from group-think or tunnel vision that reasons away all possibility of risk. Effective risk assessment should identify the proper balance of risk for which control is necessary to ensure the quality, safety, and functionality of excipients. Focusing too much on controls aimed at low-risk hazards only diverts resources and attention from high risk hazards, and can ultimately lead to an unsustainable control system and unrecognized noncompliance. 

At the other extreme, failing to acknowledge vital risk can lead to unknowingly accepting failure. Orloff explained that "risk assessment and control fundamentally rely on hypothesis, judgment, and expert opinion." He clarified that this judgment call is "to be made by experts backed with an in-depth understanding of the underlying science and a common covenant to work on what is vital." 

Manufacturers typically produce a material that is sold into diverse markets (e.g., excipients, food, cosmetics, and industrial) and their knowledge base tends to tilt toward their primary market. However, the risk assessment for excipients is unique because of their use in drug products. Risk assessment for use in food or chemical applications do not properly account for the risk unique to drug-product components.  

Many industry manufacturers and users of excipients rely on good manufacturing practices (GMPs) coupled with hazard analysis critical control point (HACCP) plans for food-ingredient manufacturers or failure mode effect analysis (FMEA) for chemical manufacturers. These tools may provide adequate controls to ensure that food is safe for human consumption or that an ingredient quality is sufficient for household products. Implementing these tools for excipients used in drug products, however, may not be adequate to ensure patient safety.  

Excipients share some similar hazards to food, but they also have a risk associated with their function in drug-product formulations and manufacturing. The act of a physician prescribing a medicine for a patient is the result of a risk assessment that concluded the benefit of taking this medication is greater than the consequence from lack of treatment. Under these conditions, a patient suffers harm when the drug product does not function as intended or is not available in the market. A patient may be harmed not only as a result of the excipient's composition, but also by potential variation in an excipient's characteristics. This variation can result in erratic performance in the drug-product formulation. 

FDA has recognized the additional risk for excipients used in drug products. 21 

 314.94(a)(9) includes a requirement that new drug applications (NDAs) show that inactive ingredients (i.e., excipients) are safe. In addition, drug manufacturers must provide information in the NDA demonstrating that the inactive ingredients do not affect the safety or efficacy of the drug product. Over-the-counter drug-product manufacturers as defined in 21 

 330.1(e) must demonstrate that suitable inactive ingredients are safe and do not interfere with the effectiveness or quality of the drug product.  

Food GMPs and HACCP do not address all the potential risks excipients pose in drug-product formulations. The use of excipients may cause failed quality release testing of a finished drug product, but may not necessarily pose a safety risk when used in a food product. In addition, a patient can suffer harm if the excipient has an adverse effect on the drug's quality after it is released onto the market. For instance, an excipient can have a slow interaction with the drug's active pharmaceutical ingredient (API), reduce the product's shelf life, or alter the API release during the digestive process. 

ICH Q9 defines risk as "a combination of the probability of occurrence of harm and the severity of that harm," and defines harm as "damage to health, including the damage that can occur from the loss of product quality or availability" (1). Excipients have the potential to harm patients in two ways: 

• Introduction of a hazard (i.e., common to many uses) 

–Chemical (toxicity, physiological effect)			

• Adversely affecting drug product availability or performance (unique to excipients)

		–Finished drug product manufacturing failure (e.g., friability of tablets, dissolution, blending) 

–Dosage of API (e.g., bioavailability, potency, changes in modified release). 

The risk-assessment model recommended in ICH Q9 identifies three steps: risk identification (define the potential harm), risk analysis (probability and severity of the potential harm), and risk evaluation (combine the two together). The output enables relative ranking by criteria used in decisions to accept or mitigate the risk. Excipient risk assessments for harm resulting from microbiological, chemical, or physical hazards parallel those for food ingredients and additives. These hazards typically result from failures during excipient manufacture and distribution. There is potential for harm to the patient in all formulations, but the risk may be heightened by the route of administration of the drug product. The potential for an excipient to adversely affect the drug product's availability or performance depends on the formulation and is a function of both the characteristic of the API and the role of the excipient in the formulation. There is no comparable risk in the food realm. 

 Figure 1: Dividing the process diagram into the realization, transfer, and use of the excipient product yields three categories useful for excipient risk assessment.			

The author describes key considertions for a complete risk-assessment model and provides insight into a pending IPEC guideline in this area.

Pharmaceutical Technology-04-01-2011

Audio: Excipient Functionality and Continuous Manufacturing

Pharmaceutical Technology, April 2011 Solid Dosage Supplement (PDF)

Exploring Excipient Functionality

Correlating Die-Filling Performance with Powder Properties

Total Excipient Control: A Pathway to Increased Patient Safety

Innovations in Tablet Coating

Risk Assessment for Excipients for Enhanced Patient Safety

Exploring Nanotechnology in Drug Delivery

Oral-Absorption-Enhancing Drug-Delivery Technology