Solid Dosage and Excipients

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Solid Dosage and

Excipients

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PharmTech .com

Solubility

s6 Meeting Solubility Challenges

Patricia Van Arnum

formulation

s10 Advances in Taste-masking

Summary of BASF Webcast

powder technology

s12 Powder Testing Techniques for Tablet Manufacture

Tim Freeman and Jamie Clayton

continuouS proceSSing

s18 Continuous Processing in Solid Dosage Manufacturing

Patricia Van Arnum

tableting

s22 Multilayer Tablets: Key Challenges and Trends An Industry Rountable featuring IMA Kilian, Elizabeth

Companies, Natoli Engineering, and Tedor Pharma

anticounterfeiting

s34 Physical-Chemical Identifiers: A Q&A with FDA on the Final GuidanceModerated by Angie Drakulich

excipient gmp

s38 The American National Standard for Excipient GMPIrwin Silverstein

riSk aSSeSSment

s42 Standardized Excipient GMPDale Carter

s46 Ad Index

Issue Editors: Patricia Van Arnum and Angie Drakulich

Cover: Compositing by Dan Ward; Images: Foodcollection RF/Getty Images

SOLID DOSAGE AND EXCIPIENTS 2012

EDITORIAL

Editorial Director Angie Drakulich [email protected]

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Art Director Dan Ward

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Dow CARBOWAX™ SENTRY™ PEGs are the best

choice for pharmaceutical applications. Why?

• Innovation - Dow has been developing innovative solutions for over 100 years.

Our latest innovation being Low Aldehyde grades for gelatin encapsulation or

formulations where impurities can be detrimental to stability and shelf life.

• Flexibility - Available in multiple forms: liquid, powder, granular and flake, as well as

various viscosities and melting points to optimize formulations.

• Performance - Proven success in applications ranging from Active Pharmaceutical

Ingredients (APIs) in laxative and colonic lavage formulations, to versatile excipients

used in tablets, ointments and creams, gelatin capsules and liquid medications,

and suppositories.

• Compliance - Conforms to NF, FCC, select European Pharmacopoeia (EP) Macrogols,

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s6 Pharmaceutical Technology Solid doSage & excipientS 2012 PharmTech .com

Solubility

The solubility of an API plays a crucial role in drug dis-position because the main pathway for drug absorp-tion is a function of permeability and solubility. Poor aqueous solubility is caused by two main factors: high

hydrophobicity and highly crystalline structures. The aqueous solubility of a compound plays a role in its success or failure as a drug candidate. Better solubility results in better absorption in the gastrointestinal tract, reduced dosage-level requirements, and better bioavailability. In the development phase, poor solu-bility can lead to inadequate exposure in efficacy and toxic-ity studies. Higher dosages required to compensate for poor solubility can lead to side effects, food effects, and intersubject variability. It may drive up overall costs for drug development and production and lead to poor patient compliance because of the higher doses required to achieve a therapeutic effect (1). As pharmaceutical companies attempt to resolve these issues, contract-service providers and excipient suppliers are seeking to meet these challenges through targeted offerings.

Strategies for improving solubilityBoth physical and chemical methods can be used to improve drug solubility, Chemical methods to improve solubility in-clude developing more soluble prodrugs or improving solubil-ity through salt formation. Physical methods include microni-zation or nanosizing, producing a polymorph, changing the crystal habit, complexation, solubilization through self-micro-emulsifying drug-delivery systems, and solid dispersions (1).

The terms solid solution and solid dispersion define related compositions in which at least one active ingredient is dis-persed in an inert matrix. In solid dispersions, separate re-gions of drug and polymer exist throughout the matrix, and the drug may be crystalline or be rendered in its amorphous state. A special subset of solid dispersions, solid solutions, re-fers to the case in which drug–polymer miscibility is attained at the molecular level, and the drug exists in its amorphous form. Pharmaceutical polymers are used to create this matrix. Polymer selection is based on many factors, including physi-cochemical (e.g., drug–polymer miscibility and stability) and pharmacokinetic (e.g., rate of absorption) constraints (1, 2).

Solid dispersions may be made through mechanical acti-vation (i.e., cogrinding), coprecipitation, freeze drying, spray drying, melt extrusion, and KinetiSol technology (DisperSol Technologies), a fusion-processing technology. The solid- dispersion components consist of the API, the polymer, plas-ticizers, stabilizers, and other agents. Various polymers may

Meeting Solubility ChallengesPatricia Van Arnum

As drug-discovery and high-throughput screening

methods increase the diversity and number of

potential lead drug candidates, formulation

scientists are tasked with the challenges of

addressing the problem of poorly water-soluble

drugs. Pharmaceutical companies, equipment

providers, contract-service providers, and

excipient manufacturers apply various approaches

for improving solubility. The article examines

some recent developments.

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Pharmaceutical Technology Solid doSage & excipientS 2012 s7

be used in solid dispersions. These include methylacrylate polymers, polyvinyl acetate, polyvinylpyrrolidone, copo-vidone, poly-(ethylene-vinylacetate-vinylcaprolatam), and cellulose derivatives (e.g., hypromellose acetate succinate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, ethyl cellulose, and methyl cellulose) (1).

Hot-melt extrusionHot-melt extrusion is used to disperse APIs in a matrix at the molecular level to form solid solutions and is used as a method to improve solubility of poorly water-soluble drugs (3). Evonik has developed a system, Melt Extru-sion Modeling and Formulation Information System (MEMFIS), as a predictive modeling tool in developing hot-melt extrusion formulations. MEMFIS helps in selecting initial formulations with no API consumption, using math-ematical models and algorithms based on solubility param-eter theories (i.e., hydrogen bonding and polar and dispersive forces). MEMFIS uses chemical structures, solubility param-eters, physicochemical properties, and a myriad of process-ing conditions to suggest initial formulation components and process settings for a hot-melt extrusion formulation (1).

In terms of miscibility estimation, for example, MEMFIS evaluates which excipients have higher potential to form a solid solution by assessing the drug miscibility of a given excipient in comparison to other excipients. The qualitative method, (i.e., which excludes hydrogen-bonding capabil-ity in the evaluation) considers the drug miscibility with an excipient in comparison to other excipients to make the determination of whether one excipient is more or less miscible. Only dispersive interactions are considered. Qualitative-only methods may lead to the exclusion of valu-able excipients from the screening studies that could poten-tially form strong hydrogen bonds with the APIs (1).

In the quantitative evaluation in the MEMFIS, which is a deeper analysis, in addition to polar and dispersive

interactions, the specific possible hydrogen-bonding in-teractions are investigated at a molecular level to derive a quantitative expectation in terms of drug–excipient mis-cibility in a binary system. In this quantitative assessment, additional specific hydrogen-bonding capability is consid-ered. This involves considering polymers from a monomer perspective (i.e., meaning the composition of the polymer) and specifying the type of hydrogen bonding that could be involved and its impact on the solubility parameters. Solubility-parameter estimation and molecular-interaction considerations are important tools in estimating first for-mulations in solid-dispersion product. High-throughput screening is accomplished based upon molecular structure, intra- and inter-molecular bonding, and their impact on solubility parameters (1). In addition to MEMFIS, Evonik is positioned in solid-dispersions through its methylacry-late polymers (Eudragit). Several late-stage products have been developed with these excipients in solid-solution for-mulations. Evonik has both hot-melt extrusion and spray-drying capabilities.

Other companies are advancing their hot-melt extrusion capabilities. In October 2011, Ashland Specialty Ingredients, which acquired International Specialty Products (ISP) in 2011, announced it was adding a GMP hot-melt extruder at its Columbia, Maryland, R&D center to better serve phar-maceutical companies working with poorly soluble drug compounds. The 180-mm Leistritz extruder allows com-panies that seek to commercialize drugs, which are made more soluble with dispersions from Ashland, to scale up to GMP clinical and commercial quantities produced by hot-melt extrusion. Ashland planned to finish installing and testing the equipment in the fourth quarter of 2011 and to begin a full-service offering early in 2012. The company has an existing extruder at its Wilmington, Delaware Research Center. With the addition of the extruder, Ashland is able to conduct kinetic-solubility and polymer-screening tests

Thin-film technology advances as a specialized oral dosage form

Thin-films represent a highly specialized solid dosage form, and although

used in over-the-counter products, this dosage form in prescription drug

products has been limited. Several companies are seeking to advance thin-

films in prescription products.

In August 2011, the specialty pharmaceutical company MonoSol Rx

announced plans to develop a second oral film product, KP 415, a prodrug

of methylphenidate, a commonly used medication for treating attention

deficit disorder. MonoSol Rx is partnered with the biopharmaceutical

company KemPharma on the project. MonoSol Rx’s PharmFilm technology is

used to deliver drugs in lingual, sublingual, and buccal dissolving films

MonoSol Rx partnered with Strativa Pharmaceuticals, the proprietary

products arm of Par Pharmaceuticals, to develop an oral soluble film for

Zuplenz (ondansetron), a drug to treat nausea and vomiting associated with

chemotherapy and radiation. The drug, approved by FDA in 2010, was the

first soluble film approved by FDA as a prescription medication, according

to MonoSol Rx. The FDA approval was granted based on clinical-study data

comparing the bioequivalence of Zuplenz 8 mg to Zofran ODT (orally dissolving

tablet) 8 mg. The pharmacokinetic results of these studies demonstrated

that a single dose of Zuplenz, taken with or without water and under fed

and fasting conditions, was comparable to Zofran ODT. In June 2008, Strativa

and MonoSol Rx entered into an exclusive licensing agreement under which

Strativa acquired the US commercialization rights to Zuplenz oral soluble film.

In January 2012, MonoSol Rx formed a joint venture with Midatech,

a company developing nanomedicines, which is focusing on the

commercialization, through partnering or licensing, of products that have

combined the intellectual property of the companies’ respective technologies

for the primary treatment of diabetes. The companies recently reported that

they are conducting a Phase I clinical study of their most advanced candidate

that uses insulin-passivated gold glyconanoparticles (i.e., MidaForm insulin)

formulated into PharmFilm for buccal delivery. In November 2011, Midatech

received regulatory approval for a first-in-human study of MidaForm insulin

delivered transbuccally. Phase I results are expected in the first half of 2012.


using both spray drying and hot-melt extrusion techniques to determine the best solubility solution in clinical trials. In October 2009, ISP launched a drug-solubility initiative that focused on solubilization technologies that involved excipients, formulation, and related processing services, which included solid-dispersion technology, both hot-melt extrusion and spray drying. In 2009, ISP partnered with the equipment manufacturer Coperion for advancing hot-melt extrusion technology.

In February 2012, the CDMO Bend Research formed a licensing agreement with Eli Lilly under which Lilly gains access to Bend’s proprietary spray-dried dispersion technol-ogy, which is designed to improve the bioavailability of com-pounds with low aqueous solubility. In addition, as part of an already existing agreement with Lilly, Bend Research will continue to provide formulation, development, analytical, engineering, and manufacturing services to Lilly to support its preclinical and clinical development programs. In August 2011. Bend Research also formed a collaboration with the CDMO Xcelience for oral solid-solubilization formulation solutions and clinical-supply manufacture.

In July 2011, the CDMO Pharmaceutics International (Pii) added hot-melt extrusion to its formulation and process-development solutions capabilites. The company purchased a 16-mm and an 18-mm Leistritz twin-screw extruders. This investment enables Pii to carry out feasibility studies to pilot-scale cGMP productionfor Phase I and II clinical-trial materials using hot-melt extrusion.

In 2009, BASF launched its polymeric solubilizer, So-luplus, which is used in hot-melt extrusion applications. In 2010, the company partnered with GEA Niro to allow BASF to make cGMP spray-drying tests and pilot produc-tions of APIs at GEA’s test station in Copenhagen. Dow Wolf

Cellulosics offers several expicients for hot-melt extrusion applications, including poly (ethylene) oxide resins (e.g., Polyox) and cellulosic derivatives [e.g., Ethocel (ethylcellu-lose ethers)] and Methocel (cellulose ethers).

In April 2011, the CDMO Pharmatek Laboratories added spray drying to its drug formulation and manufacturing capabilities. The company purchased a Buchi B-290 Mini Spray Dryer for formulation feasibility studies and small-scale clinical manufacture.

Academic researchResearchers at Purdue University recently reported on an extrusion-based approach where the dissolution rate of poorly soluble drugs (griseofulvin, phenytoin, and spirono-lactone) was improved through solid crystal suspensions. The drug and mannitol were coprocessed in a hot-melt ex-trusion operation. The resulting product was a mixture of the crystalline drug and crystalline excipient, with up to 50% (w/w) drug load. The in vitro drug release from the obtained solid crystalline suspensions was more than two orders of magnitude faster than that of the pure drug. The researchers reported that because the resulting product was crystalline, the accelerated dissolution rate did have the physical stability concerns as with amorphous formu-lations. The researchers reported this approach is useful in situations where the drug is not a good glass former or in cases where it is difficult to stabilize the amorphous drug (4).

References 1. P. Van Arnum, Pharm. Technol. 35 (10), 50–56 (2010). 2. J. Doney and J. Yang, Pharm. Technol. 32 (7), 96–98 (2008). 3. M. Karl, D. Djuric, and J. Kolter, Pharm. Technol. 35 (5), 74–82

(2011). 4. M. Thommers et al., Mol. Pharmaceutics 8 (3), 727–735 (2011). PT

Solubility

Several characteristics of peptides limit oral bioavailability. These molecules

are relatively large in size. The hydrophilic nature of peptides limits the

absorption of these molecule in the gastrointestinal tract, and peptides are

susceptible to degradation by enzymes in the stomach and intestine (1). To

address these problems, Unigene Laboratories, a company involved in the

design, development, and manufacture of peptides, has developed an oral

peptide delivery platform.

The company’s technology platform, Enteripep, involves the use of

an enteric coating to permit passage through the stomach into the

small intestine. An organic acid inhibits proteases, and an absorption

enhancer facilitates the uptake of the peptide by a paracellular transport

mechanism. Absolute bioavailability ranging from 1% to greater than

20% can be achieved (2).

In 2011, Unigene had two late-stage oral peptide programs successfully

advance in the clinic. Ostora, the company’s oral calcitonin licensed

to Tarsa Therapeutics, successfully completed a Phase III study. The

company expects to submit a new drug application by the end of

2012. The company’s oral formulation of a recombinantly produced

parathyroid hormone (PTH) analog for the treatment of osteoporosis in

postmenopausal women completed a Phase II study in 2011. In November

2011, Unigene announced positive top-line results of its Phase II clinical

study evaluating an experimental oral PTH analog for the treatment

of osteoporosis in 93 postmenopausal women. The study achieved its

primary endpoint with statistical significance and was conducted by

Unigene as part of now terminated agreements with GlaxoSmithKline

(GSK). In December 2011, GSK returned the rights to the drug to Unigene.

Unigene, which is seeking a new licensing partner for the drug, sees

the oral form of PTH as an alternative to injectable-delivered PHT. The

PTH injectable market alone represents approximately $1 billion with

sales expected to double over the next two to three years, according to

estimates from Unigene.

Sources 1. Unigene, ÒProprietary Drug Delivery,Ó company information, www.

unigene.com/proprietary-delivery-technologies/, accessed Feb. 13, 2013.

2. N. Mehta, presentation at the 6th Annual Obesity and Diabetes Drug

Development Summit (Arlington, VA, July 20Ð21, 2010).

Emerging technologies: oral peptide delivery

Sustainability

At DSM, our purpose is to create brighter lives for people today and

generations to come. This mission is supported by sustainability as

a core value and one of four pillars in our Quality for Life™ commitment.

Its philosophies and metrics are evident in everything we do, highlighted by a

top ranking in the Dow Jones Sustainability Index in the global chemical

industry for 10 consecutive years. Sustainability is also

an increasingly valued criterion for vendor selection, so it’s not

only a responsible approach, but a strategic business driver.

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Tel: +1 973 257 8011

www.dsmpharmaceuticalproducts.com

www.dsm.com

Quality

Reliability

Traceability

Sustainability


Formulation

Advances in Taste-maskingPatricia Van Arnum

Taste-masking of solid dosage and liquid drugs is a challenge for pharma-ceutical manufacturers. Most APIs are unpleasant or harsh tasting leading to patient noncompliance. This challenge affects all age groups, but is specifi-cally problematic for pedi-atric patients. The global market for pediatric drugs

and vaccines is forecast to reach $85 billion by year 2017, according to data from Global Industry Analysts. The US is the largest market for pediatric drugs followed by West-ern Europe. Implementing taste-masking programs into the drug-manufacturing process is crucial to avoid losses due to noncompliance. Pharmaceutical manufacturers are faced with challenges in life-cycle management, cost con-trol, global regulations, and patent protection.

In a recent editorial webcast, Pharmaceutical Technol-ogy examined formulation-development strategies in product life-cycle management, including specialized for-mulations such as pediatric formulations, and the specific technical issues that may evolve in excipient selection and functionality, including taste-masking and moisture pro-tection, to develop an orally palatable product.

Participating in the webcast were: Avinash Thom-bre, PhD, research fellow, pharmaceutical sciences with Pfizer Global Research and Development, who discussed life-cycle management and new dosage form options; Karen C. Thompson, PhD, distinguished senior inves-tigator, pharmaceutical sciences at Merck & Co., who discussed insight into pediatric formulations and re-lated dosage forms; and Nigel Langley, PhD, MBA, head of North American technical sales, Pharma Ingredients & Services, BASF, who discussed novel taste-masking excipient solutions. The webcast may be found at www.PharmTech.com/Webcasts, see Taste-masking in Formu-lation Development.

In 2011, BASF launched Kollicoat Smartseal 30 D, an aqueous disperson of a film-forming polymer with taste-masking and moisture-barrier applications. The excipient is highly impermeable to water vapor, which helps pre-serve the potency of sensitive active ingredients, according to the company. The polymer is stable in saliva and spe-

cifically soluble in gastric juice. These properties allow for effective protection from unpleasant taste in the patient’s mouth and rapid release and onset of active ingredient action in the stomach.

In October 2011, BASF and Colorcon announced a collaboration for the development of future film-coating systems using BASF’s Kollicoat Smartseal 30 D and a new Colorcon preformulated additive. Colorcon developed the preformulated additive system for use with Kollicoat Smartseal 30 D to enable efficient preparation and ap-plication of this polymer in taste-masking applications. The preformulated additive lowers the number of materi-als to be dispensed by 50% and reduces the preparation time by almost 40%, according to an Oct. 21, 2011, BASF press release.

“We have chosen Kollicoat Smartseal 30 D because it is the best-in-class reverse enteric polymer for taste mask-ing”, said Kamlesh Oza, general manager, film coating at Colorcon, in the BASF press release. “Kollicoat Smarts-eal 30 D is the first water-based dispersion having both taste-masking and moisture-barrier properties. It was de-veloped to simplify and accelerate aqueous film coating operations and opens new doors for formulating tablet, pellet, and particle coatings. Our collaboration to develop the additive will bring batch-to-batch color consistency, performance, speed, and simplicity, enabling easy recon-stituting of the film former in pharmaceutical coating operations while maintaining functionality,” he said.

Kollicoat Smartseal 30 D is part of BASF’s existing tablet coatings portfolio. Under the Kollicoat brand, BASF markets a range of coating polymers and copoly-mers that are used to coat tablets, capsules, and pellets and to control the release of drugs from solid-dosage forms. The Kollicoat family includes: Kollicoat IR and Kollicoat Protect instant-release coatings, Kollicoat IR Color Coating Systems, Kollicoat MAE enteric coatings, Kollicoat SR 30 D sustained-release coatings, and the new Kollicoat Smartseal 30 D protective coatings. PT

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Powder Technology

In tablets, the active pharmaceutical ingredient (API) is often only a tiny proportion of the finished product. The steps that precede the tablet press are designed to incor-porate the API within a blend that processes efficiently

to produce tablets of the required quality. Excipients include fillers, as well as components that play a more active role in processing, such as glidants to improve powder f low and lubricants that reduce ejection force and prevent adherence to the press.

These raw ingredients may be screened, granulated, dried, milled, classified and blended, often in a number of steps, to produce feed for the tablet press. Batch processing, in which a defined amount of material is processed and then tested to confirm its suitability for the next step, is common.

Each ingredient and unit operation is a potential source of variability arising from any number of factors including:•Raw materials•Human intervention (especially if the plant is manually

controlled)•Sampling and analytical test method variability•Environmental influences•Process equipment capabilities and calibration limits (1).Materials are tested after each processing step with the

aim of quantifying variability, which raises the question of how to characterize “in-process” materials to ensure success. Because the tablet press is at the end of the line, any sources of variability along the way will tend to act cumulatively at the tablet press.

Effective management of variability relies first on being able to detect a problem. This means that a specification used to define acceptability—in a feed or after a process-ing step— must reliably identify a material that will fail to process as required in a subsequent step or that will go on to produce a substandard product. Such specifications must be based on properties that closely correlate with the aspects of performance that are critical to success. This approach relies on identifying and measuring powder properties that have a defining influence on the efficiency of the operation and the quality of the final product.

Powder Testing Techniques for Tablet ManufactureTim Freeman and Jamie Clayton

Drugs in solid dosage form continue to be

universally popular, with the majority of

pharmaceutical actives still delivered as tablets.

Successful tablet manufacture relies on filling a

die with a uniform, loosely packed blend and then

compressing that powder to form a consistent,

stable product. A greater understanding of the

powder properties that relate to performance in

the press and which upstream processes influence

powder properties enables improvements to

be made at the appropriate processing stage(s),

leads to improved throughput, and enhances

the quality of the finished product. This article

considers the different conditions to which the

powder is subjected in the tableting process,

and discusses which powder properties should

be measured to accurately reflect likely powder

behavior in the process.

Tim Freeman* is managing director and Jamie Clayton

is operations manager at Freeman Technology, 1 Miller

Court, Severn Drive, Tewkesbury, Gloucestershire,

GL20 8DN, United Kingdom, tel. +44(0)1684.851.551,

fax. +44(0)1684.851.552, [email protected], www.

freemantech.co.uk

*To whom all correspondence should be addressed.

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Analyzing the tableting processPowder behavior is influenced by an array of different vari-ables, including primary parameters such as particle size and shape, as well as system factors such as extent of con-solidation and aeration. This complexity makes it difficult to predict behavior. To develop a secure basis for process op-timization, it is necessary to select powder property charac-terization techniques that simulate the process environment, because it is difficult to reliably infer performance from test data acquired under conditions that are not representative of those applied during processing.

Manufacturing tablets from a blend tends to be a single integrated process. However, closer analysis reveals four dis-tinct stages, particularly in terms of the conditions applied to the powder. These are:•Discharge from the feed hopper•Flow into and through the feed frame•Die filling•Compression, followed by ejection.Hopper discharge. Tablet manufacture begins with dis-

charge of the blend from the hopper, ideally at a consistent, controlled flow rate. Material f lows under gravity, at rela-tively low flow rates, into the feed frame. In the hopper itself, moderate stress is imposed by the weight of the stored pow-der. The resulting consolidation may inhibit flow, either be-cause of interactions between the vessel and powder or as the result of powder-powder interactions. Shear strength and wall friction are therefore highly relevant powder properties.

Feed frame flow. The hopper discharge is routed to the feed frame via enclosed pipe work that provides containment. The ease with which the blend flows under gravity is impor-tant here, but so too is the permeability of the powder (2). A blend with low permeability that resists the backflow of air necessary for smooth flow will tend to pulse or ‘slug’ into the feed frame (see Figure 1). This can result in erratic pressure

that varies at a relatively high frequency. The tablet press weight control system cannot adequately compensate, which results in variable tablet weight. In contrast, more perme-able blends tend to exhibit more consistent flow, ultimately delivering a more uniform density to the feed frame and a more consistent final product.

Die filling. From the feed frame, powder is swept into the dies to ensure a complete fill. Here the blend is moderately to loosely packed, but sheared at relatively high speeds as the paddles of the frame rotate. Agglomeration and attrition are both potential problems, exacerbated by the need to recycle powder around this part of the process. Both can lead to seg-regation of the blend, giving rise to non-uniformity in the finished tablet. Attrition additionally gives rise to dusting, creating fines that can compromise processing efficiency and the properties of the finished tablet.

In the feed frame, the powder f lows under gravity but, depending on the design of the paddles, there may also be a significant element of “forced flow.” Angling the sweeping paddles can help to force the powder down into the dies to improve filling efficiency. While optimizing the flow regime in the feed frame improves consistency and the rate of die filling, doing so relies on understanding how the powder flows under different conditions and, in particular, the ma-terial’s response to forcing conditions.

In addition, the response of the powder to air is critical for consistent die filling. A permeable blend that quickly re-leases entrained air will settle rapidly and efficiently fill the die. Simultaneously, air can provide lubrication and promote

flow in the feed frame. Therefore, a material that releases air too easily may not flow consistently. Understanding exactly how the powder responds to air can be critical in optimiz-ing die filling.

Compression. During the final compression step, the pow-der plug is subject to high stress. Here, the compressibility of the powder is relevant because it quantifies how the move-ment of the punches will impact the powder. In addition, adhesivity indicates how likely it is that material will stick to the tablet press tooling.

Choosing the best powder characterization techniquesSuccessful processing requires a powder that is compatible with all stages of the process. Because it is important to un-derstand how the powder will behave under many different conditions, applying a single powder testing technique may

Specifications must be

based on properties that

correlate with critical

performance aspects.

Figure 1: More permeable powders tend to flow consistently

from a hopper, while those that are less permeable can give

rise to a low rate, ‘pulsing’ flow that is detrimental to process

efficiency and product quality.

High Permeability

High & ConsistentFlow Rate

Low & ‘Pulsing’Flow Rate

aerating

Fully aerated (fluidized)

Low Permeability

Fully de-aerated(maxconsolidation)


not give adequate information. Historically, the pharma-ceutical industry has relied on parameters such as Hausner Ratio and Carr’s Index, which are both derived from tapped density techniques. More recently, the industry has begun to use shear testing.

These approaches do have some relevance when trying to access information to support optimization of the press.

Shear testing, for example, was devel-oped, and remains widely used, for the design and troubleshooting of hop-pers. This test provides valuable shear strength data that is relevant to design and operation of the feed hopper and to the compression stage, in which ap-plied stresses are even higher. However, shear testing may not be the best tech-nique for generating data to support other parts of the tablet manufactur-ing process, in which applied stresses are far lower.

For example, the shear data pre-sented in Figure 2a for vanillin and ethylvanillin classifies them as closely similar. However, as shown in Figure 2b, the dynamic flow energy measure-ments tell a different story, suggesting that the materials can behave differ-ently in certain circumstances. Flow energies are generated by measuring the axial and rotational forces acting on a paddle as it rotates through a pow-der sample (3). Downward rotation of the paddle imposes a forcing, bulldoz-ing action while an upward traverse measures a f low energy more closely associated with gravity induced f low. The data suggests that while these two materials may behave similarly in the hopper, and in terms of how they co-here in the finished tablet, they will be-have very differently in the feed frame. The ease with which the materials flow into the feed frame, and subsequently into the die, as well as their response to a range of blade designs, are all likely to be different.

Similarly, tapped density measure-ments can differ from f low energy measurements. Although tapped den-sity measurements do detect changes that indicate differences in powder properties, they are far less sensitive than dynamic techniques in specifi-cally measuring f low properties (see Figure 3). Variability in a material,

which could go on to impact f low behaviour in the tablet press, might be undetected by tapped density measurements.

Looking across the tablet-making process in its entirety highlights the properties that could be measured to optimize performance at each step. These include:•Shear properties—for the design, operation, and trouble-

shooting of hoppers

Figure 2: Shear data classifies these two excipients as closely similar while flow

energy measurements show that in certain circumstances they can behave quite

differently.

vanillin

ethylvanillin

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(b)

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Powder Technology

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•Bulk properties such as permeability and compressibil-

ity—to assess the response of the powder to air, the ease with which displaced air will be dispersed, and how the blend will be impacted by compression•Dynamic properties that directly quantify flowability

under different conditions—for optimizing flow through the feed frame, assessing the impact of different paddle designs, investigating the effect of air on powder f low-ability, and quantifying de-aeration behaviour.Dynamic testing can also be used to assess powder stabil-

ity and is therefore a useful tool for investigating the likeli-hood of attrition, segregation, and/or agglomeration.

Together these measurements form a database of prop-erties that can be used to tightly define an optimal blend specification. Furthermore, such data would support in-vestigation into which parameters in upstream processes ultimately dictate performance in the press and the quality of the final product. Such strategies are highly beneficial in pushing towards more efficient manufacture on the basis of secure knowledge.

Conclusion

Within the pharmaceutical industry there is increasing emphasis on processing efficiency and more effectively controlled manufacture. In production, it is impossible to eliminate all the possible sources of variability, but it is feasible to compensate for them and control their impact. This relies on identifying, measuring, and controlling those parameters that define processing efficiency and the quality of the finished product.

In solid-dosage manufacture, achieving this goal re-quires a relevant and sensitive powder testing toolkit capable of reliably generating parameters that can be di-rectly correlated with process performance. Key to this is the ability of a technique to effectively simulate the specific processing environment, which, as an analysis of tableting reveals, can vary considerably. Instruments that combine established techniques, such as shear and bulk property testing, with newer methodologies, such as dynamic testing, can be valuable. The user can then tailor testing to the specific application, and access the most complete information for process design, optimiza-tion, and control.

References

1. M. Glodek et al., “Process Robustness: PQRI White Paper,” online,

www.pqri.org, Oct., 2005.

2. G. Carlson and B. Hancock, AAPS Annual Meeting and Exposi-

tion (Atlanta, GA, 2008).

3. R. Freeman, Powder Technol. 174 (1–2) 25-33 (2007). PT

Figure 3: For this system, tapped density data are less

sensitive than flow energy measurements in detecting

changes in powder flowability.

Increased Tapping

Density change ~ 40% (max)

Den

sity

Flo

w E

nerg

y Flow Energychange > 1000%

Although tapped density

measurements detect changes

that indicate differences in

powder properties, they are

far less sensitive than dynamic

techniques.

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continuous Processing

The pharmaceutical industry, equipment and machinery companies, and academic researchers are investing to develop applications in continuous processing for drug production. Supported by quality-by-design principles,

a regulatory environment that is encouraging the industry’s move to continuous manufacturing, and lured by the promise of improved production economics and greater operating ef-ficiencies, the industry is moving forward with select projects in continuous solid-dosage manufacturing.

Continuous granulationAlthough pharmaceutical production is a batch-processing op-eration, specific unit operations in solid-dosage manufacturing, such as milling or tablet compression, may be run in semicon-tinuous and continuous processing steps (1). The feasibility of developing continuous processes for specific unit operations requires advances in pharmaceutical equipment design and operation. For example, to make continuous mixing, granula-tion, and drying possible for small-scale operations, such as in the pharmaceutical industry, systems need to be developed with limited or no start-up and shutdown waste to enable reaching steady state in an extremely short time (2). A commercial ex-ample is GEA Pharma Systems’ ConsiGma continuous granula-tion, and drying system. Designed in a modular way, the sys-tem consists of a patented twin-screw granulator, a segmented continuous fluid-bed dryer, and a granule-conditioning unit to prepare granules for a tablet press (2).

One advantage of continuous operations is the elimination of scale-up, which may be difficult overall and in specific op-erations, such as granulation (1). As hot-melt extrusion is gain-ing popularity for solubilization of insoluble drugs, twin-screw extrusion also is gaining attention as a continuous alternative to traditional high-shear granulation. This continuous process enables faster throughput and easier scale-up. Ashland Specialty Ingredients recently presented results on how hydroxypropyl-cellulose (Krucel), povidone (Plasdone), and hypromellose (Benecel) performed in continuous low-temperature extrusion granulation as compared with traditional wet granulation. The results showed twin-screw extrusion as a promising method for

Advancing Unit Operations For Continuous ProcessingIn Solid-Dosage ManufacturingPatricia Van Arnum

Continuous manufacturing is gradually advancing

through select projects of pharmaceutical

companies and researchers in academia.

Granulation is one processing step moving to

a continuous mode. The article examines some

recent developments for this process step and for

continuous manufacturing overall.

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high-dose formulations and highlighted how tablets made by means of extrusion showed improved strength and low friability compared to traditional wet granulation, according to an Oct. 13, 2011, company press release.

Researchers at Ghent University in Belgium and Com-plutense University in Madrid recently evaluated the strengths and weaknesses of several complementary process analyti-cal technology (PAT) tools implemented in a continuous wet- granulation process, which was part of a fully continuous from powder-to-tablet production line (3). The use of Raman and near infrared spectroscopy and a particle-size distribution analyzer was evaluated for the real-time monitoring of critical param-eters during the continuous wet agglomeration of an anhydrous theophylline−lactose blend. The solid-state characteristics and par-ticle size of the granules were analyzed in real-time and the critical process parameters influencing these granule characteristics were identified. The temperature of the granulator barrel, the amount of granulation liquid added and, to a lesser extent, the powder feed rate were the parameters influencing the solid state of the API. The researchers reported that a higher barrel temperature and a higher powder feed rate resulted in larger granules (3).

Researchers at Pfizer and the University of Cincinnati recently reported on work regarding optimization for a continuous ex-trusion wet-granulation process (4). Three granulating binders in high drug-load acetaminophen blends were evaluated using

high-shear granulation and extrusion granulation. The research-ers reported that a polymethacrylate binder enhanced tablet ten-sile strength with rapid disintegration in simulated gastric fluid, and polyvinylpyrrolidone and hydroxypropyl cellulose binders produced less desirable tablets. Using the polymethacrylate binder, the extrusion granulation process was evaluated with respect to the effects of granulating liquid, injection rate, and screw speed on granule properties. Response variables consid-ered in the study included extruder power consumption (screw loading), granule bulk/tapped density, particle-size distribution, tablet hardness, friability, disintegration time, and dissolution (4).

Academic–industrial partnershipsContinuous manufacturing also is being advanced by indus-trial, public, and academic partnerships. For example, in Oc-tober 2011, FDA awarded a $35-million, five-year grant to the National Institute for Pharmaceutical Technology and Educa-tion (NIPTE), a nonprofit research center focused on pharma-ceutical product development and manufacturing, to improve drug manufacturing standards. NIPTE’s goal is to increase science and engineering-based understanding, so technologies can be developed and science-based regulations can be imple-mented. The FDA grant will in part by used to promote continu-ous manufacturing as well as other issues, such as improving small-batch production, reducing the environmental impact of

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manufacturing pharmaceutical products, and rectifying other drug-development and manufacturing problems.

NIPTE is partnered with 10 US universities involved in the pharmaceutical sciences and engineering. The member univer-sities are Duquesne University, the Illinois Institute of Technol-ogy, Purdue University, Rutgers University, the University of Puerto Rico, the University of Connecticut, the University of Iowa, the University of Kentucky, the University of Maryland–Baltimore, and the University of Minnesota.

In April 2011, the United Kingdom’s Engineering and Physi-cal Sciences Research Council (EPSRC) established the EPSRC Center for Innovative Manufacturing in Continuous Manufac-turing and Crystallization. EPSRC is the main UK government agency for funding research and training in engineering and the physical sciences. The University of Strathclyde is leading the EPSRC Center for Innovative Manufacturing in Continu-ous Manufacturing and Crystallization, which also involves the Universities of Bath, Cambridge, Edinburgh, Glasgow, Heriot-Watt, and Loughborough. Industry partners include GlaxoSmithKline, Pfizer, AstraZeneca, Fujifilm, Croda, Genzyme (now part of Sanofi), NiTech Solutions, Phoenix Chemicals, Solid Form Solutions, and British Salt.

The EPSRC Center for Innovative Manufacturing in Contin-uous Manufacturing and Crystallization has identified several key research challenges:

•Achieving precise control over manufacturing of solid particles using continuous-manufacturing technologies •Understanding the control of nucleation and growth

of particles by means of crysta l l ization under continuous flow•Developing continuous crystallization platforms, pro-

cess analysis tools, and strategies to manufacture par-ticles for different applications•Delivering the tools to control crystal structure, particle

shape, and particle-size distribution•Facilitating continuous manufacture of medicines and

nanomaterials with kinetic, cocrystallization, and im-purity control (5).

In 2007, Novartis formed a $65-million, 10-year research collaboration with the Massachusetts Institute of Technology (MIT) to launch and fund the Novartis–MIT Center for Con-tinuous Manufacturing to develop new technologies to replace the pharmaceutical industry’s conventional batch-based system with continuous manufacturing processes.

The Engineering Research Center For Structure Organic Particulate Systems, a multi-university consortium consist-ing of Rutgers University, Purdue University, the New Jersey Institute of Technology, and the University of Puerto Rico at Mayagüez, is another academic-partnership involved in continuous processing. The center, which is funded by Na-tional Science Foundation and industrial partners, includes 35 pharmaceutical manufacturers and equipment producers involved in R&D for continuous processing (2).

Researchers at Rutgers University recently reported on an en-hanced model-based control of a continuous direct-compression pharmaceutical process. The control-loop performance was as-sessed in silico, and results obtained will be incorporated into the pilot-plant facility of the continuous direct-compaction process at the National Science Foundation’s Engineering Research Cen-ter at Rutgers University. The models used in the study were ob-tained by means of a system identification from a combination of first principles-based dynamic models, experimental data, and/or literature data. The purpose of the study was to formu-late an effective control strategy at the basic/regulatory level for the integrated continuous operation of the direct-compaction process and to maintain the process at the desired set-points, taking into account the multivariable process interactions and disturbances (6).

References 1. B.L. Trout et al., Ind. Eng. Chem. Res. 50 (17), 10083–10092 (2011). 2. P. Van Arnum and R. Whitworth, Pharm. Technol. 35 (9), 44–47

(2011). 3. M. Fonteyne et al., “Real-time Assessment of Critical Quality At-

tributes of a Continuous Granulation Process,” Pharm. Develop. & Technol., online, DOI 10.3109/10837450.2011.627869, Oct. 24. 2011.

4. L. Tan et al., Pharm. Develop. & Technol. 16 (4), 302–305 (2011). 5. EPSRC, “EPSRC Center for Innovative Manufacturing in Continuous

Manufacturing and Crystallization,” www.epsrc.ac.uk/funding/cen-tres/innovativemanufacturing/Pages/imrccontinuousmanufacturing.aspx, accessed Feb. 13, 2012.

6. R. Ramachandran et al. , J. Pharm. Innov. 6 (4), 249–263 (2011). PT

Continuous Processing


Tableting

Solid dosage forms are the most popular method of drug delivery and although tablets are widely estab-lished throughout the pharmaceutical industry, this doesn’t mean it is an unmoving area. According to

a recent Pharmaceutical Tehnology poll, manufacturers are seeking to reformulate or reinvent their currently marketed solid-dose products to both renew patents and improve ef-ficacy (see Figure 1).

One possible way to achieve these goals is to reformulate tablets into more exotic forms such as multilayer tablets, fixed-dose combinations, and other innovative dosages.

Pharmaceutical Technology brought together experts in solid dosage for a special roundtable on the formulation and manufacture of multilayer tablets. We also spoke to re-searchers about fixed-dose combinations, an area that has raised controversy, regarding adverse effects. Participants in the roundtable include: Marcus Behrens, sales director at IMA Kilian; James Calvin, Elizabeth Companies; Doug Kirsch, Technical Service Manager at Natoli Engineering Company; and LakshmiDevi Ethirajan, Manager, Formula-tion Development at Tedor Pharma.

Industry demandPharmTech: How has demand for multilayer tablets altered in recent years? What factors have influenced this trend?

Behrens (IMA Kilian): Fixed-dose combination drugs are becoming increasingly popular, particularly as life-cycle management strategies seek to extend intellectual property and minimize generic exposure by creating an innovative dosage form. The multilayer tablet is a viable way to combine different actives for a synergic therapeutic effect, or differ-ent formulations of the same active in order to achieve a specific release profile. Furthermore, multilayer tablets can help avoid interactions between different drugs and opti-mize each formulation in terms of pharmacokinetics and manufacturability.

Calvin (Elizabeth Companies): The growth of high-potency and combination drug products over the last de-cade has made multilayer and tablet in tablet (core tablet)

Multilayer Tablets: Key Challenges and Trends An Industry Rountable

Experts in solid dosage discuss the formulation

and manufacture of multilayer tablets. Fixed-

dose combinations, which have raised much

controversy in the industry as experts mull the

potential for adverse effects, are also discussed.

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Tableting


hot topics in the pharma industry. These novel delivery systems have been essential not only in formulating new products, but also in helping pharmaceutical companies to extend patents.

Ethirajan (Tedor Pharma): Among other advantages, triple-combination therapy in a single-dosage form is being used to promote better treatment adherence by providing a convenient single tablet. As well as increasing patient compliance, multilayer tablets can help to reduce the cost of medication.

Future success

PharmTech: Considering the split drivers of compliance and patent extension, do you think multilayer tablets will continue to be successful in the future?

Behrens (IMA Kilian): If we think of f ixed-dose combination drugs as a way to treat two closely related diseases, or to improve compliance and thus efficacy of prescribed medicines, we believe that this trend will continue. However, multilayer tablets could be a less fre-quent option if, in the future, the drugs are designed to be mixed into a unique powder that can be processed in a standard tablet press.

Today, most combined actives are existing drugs. In the future, a higher number of combinations will be achieved with new formulations that are specifically designed to be combined from the development stage. In this case, the properties of the different compounds can be optimized to be combined, minimizing possible interactions.

Calvin (Elizabeth Companies): I believe that the de-mand for multilayer and tablet-in-tablet technology will continue for many years to come, particularly as new high-potency drugs, which are often combined with other drugs in a single multilayer tablet generate a demand for layer technology. Many matrices are incompatible with one another, but with multilayer tablets, formulators can insert an inert barrier layer between the incompatible matrices to prevent an interaction. Also, developments in the technology have made multilayer tablets easier to

produce. For instance, for core tablets, developments now enable the core to be positioned more precisely within the tablet.

Kirsch (Natoli): Multilayer tablets have been manufac-tured for a long time; more than 50 years that I know of. They are not going away.

A new possible need for layered tablets is the recent FDA draft guidance for industry on tablet scoring. Uni-form dosage and assurance that a patient is capable of splitting the tablet properly are two of its concerns. Accu-Break Pharmaceuticals developed and patented a unique method using layered tablets to address these issues. The first (bottom) layer is a drug-free placebo. The second (top) layer containing the API(s) is scored deep enough to reach the second layer. The first inactive layer is merely a holder for the active second layer and when broken, result in a uniform dose. A trilayer tablet with an inactive center layer for split dose combinations has also been developed. Simple, yet brilliant.

Ethirajan (Tedor Pharma): Multilayer technology will continue to be an option in the future for several reasons: •Pharmaceutical companies will file new patents or ex-

tend existing patents on their company name on com-bination product to win market exclusivities. •Generic-drug makers may use new technology as an

option to work around existing patents for markets product.•Advancements in the technology by equipment manu-

facturers who recognized the importance of meeting regulatory requirements to market their high speed machines for production.

Most importantly, a single tablet containing multiple medications can be both cheaper and more convenient than separate tablets.

Formulation

PharmTech: When formulating multilayer tablets, what spe-cial considerations are required for factors such as levels of fines, bulk densities, and granulation properties?

Figure 1: Demand for reformulation (PharmTech poll).

Need to renew patents

Availability of new excipients

Opportunity to improve efficacy and patient compliance

40%

11%

49%

What is driving manufacturers to reformulate or reinvent

currently marketed solid dose pharmaceutical products?

From left to right: Marcus Behrens (IMA Kilian), James Calvin (Elizabeth

Companies), Doug Kirsch (Natoli); LakshmiDevi Ethirajan (Tedor Pharma) is

not shown.


Behrens (IMA Kilian): For efficient tableting, granule f low is crucial and a certain amount of fines is needed to guarantee proper filling and binding of the tablet. It is also important that the tableting machine is designed so that the filling range can cope with bulk density. In addition, the system should avoid the carry-over of par-ticles or fines.

Calvin (Elizabeth Companies): When utilizing a tablet press with the proper powder-feed system, there is usually no need for any special considerations or factors such as levels of fines or granulation properties to be determined. The only consideration would be the bulk density of the granulation. Depending upon which layer is the lighter den-

sity granulation, it would normally be used on the first layer if the tableting press has a limitation of the upper punch penetration of the layer tamping stations that regulate the depth of fill of the consecutive layers.

Kirsch (Natoli): The level of fines must always be con-sidered, even for non-layered tablets. Excessive fines will result in poor tablet quality, as well as tool binding and tablet press overheating, which exacerbates sticking and picking issues. Although fines are a necessary evil for proper tablet compressibility, it is critical that these are kept to a minimum when compressing layered tablets oth-erwise cross contamination from one layer to the next will be increased as fines will pass under feeders and scraper blades. Bulk densities are also a consideration because light or airy granulations require increased depth of fill and precompression. Pre-compression of the first layer is required for clear demarcation lines between the layers. If the press does not have sufficient upper punch penetra-tion to pre-compress/tamp the first layer, then the desired weight may not be achieved and there will be insufficient volume in the die bore for the next layer. Some modern presses are only capable of 4 mm upper punch penetra-tion, whereas many older presses were capable of almost

“The multilayer tablet is

a viable way to combine

different actives for a synergic

therapeutic effect...,” — Marcus

Behrens, IMA Kilian

Continued on Page s28

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Tableting


PharmTech: Why have FDCs been criticized in the past?

Gupta (Imperial College London): The use of FDCs was

previously discouraged because of cost considerations, lack of

flexibility in dose titration, and doubts over the bioavailability of

the individual components (compared with the bioavailability of the

constituent components, when given separately). Another concern

was that the use of FDCs would be associated with the increased risk

of adverse events. Over the last few years, however, the findings of

several clinical trials and observational studies have refuted most of

these concerns (1–4).

Findings from recently conducted clinical trials have virtually removed

any doubts over the comparative efficacy and safety of an FDC versus its

corresponding free-drug combination. Moreover, in several situations,

the use of FDC was associated with significantly improved efficacy. For

example, in the ACCOMPLISH Trial, blood pressure control rates (within

first six months) improved significantly among previously treated

hypertensive patients, from 37% to 73%, with the use of a single pill

FDC of two antihypertensive agents. Another trial using a low-dose FDC,

STITCH Trial (Simplified Treatment Intervention to Control Hypertension),

found that those allocated to treatment with an FDC compared with the

usual care were more likely to have a better blood pressure control, with

no adverse effect on tolerability.

Other studies have also shown that the total costs (direct and indirect)

related to the use of any FDC is likely to be lower than the use of its

corresponding free-drug combination, particularly because of a reduction

of indirect costs related to disease complications. Indeed, a quick look

at the costs of available FDCs in the UK shows that the direct cost of

several FDCs is similar or cheaper than the cost of the two constituent

components given separately. Additionally, the cost to patients at the

point of delivery is cheaper with an FDC compared with the prescription

of two components separately when patients have to pay for prescription.

A recent study has also shown that costs incurred by the patient (either as

co-payment or otherwise) has an inverse relationship with adherence and

concordance with medication. Lastly, the improved and easy availability

of several different dose compositions of an FDC have made it easier for

physicians to up-titrate medications with little difficulty.

In summary, I believe, it is no longer justified to persist with an attitude

of disdain against the use of FDCs.

Udupa/Sreedhar (Manipal University): The single most

important factor that FDCs have been criticised for is dose titration.

Dose titration of one or all the active ingredients present in an FDC is

not possible, which is crucial when both actives require dose titration.

However, manufacturers have taken note of this and addressed the

problem in certain cases, but the criticism is justified because the very

existence of the FDC discourages adjustment of doses to the patient’s

needs, and may also lead to overdosing or underdosing of one or more

of the active ingredients present. Moreover, busy prescribers may not

notice the dose of each active ingredient present in an FDC and it could

encourage polypharmacy.

PharmTech: Despite criticism, some data have suggested that

compliance is increased. Could you explain why you agree or disagree

with this statement?

Gupta (Imperial College London): I agree that there is a

significant body of evidence confirming directly or indirectly that

the use of an FDC is associated with improvement in compliance.

Several observational studies have shown an inverse relationship

between the number of prescribed medications and concordance

with them. A few qualitative surveys on patient perception have

largely produced supportive data, suggesting that the use of an FDC

would be more convenient for patients, and encourage compliance

and adherence with medications. The findings of our meta-analysis,

using evidence from cohort studies and clinical trials, have confirmed

previous indirect findings: our analyses found that, compared with a

free-drug combination, the use of an FDC was associated with a 21%

significant increase in compliance and a 54% increase in persistence

with therapy.

Udupa/Sreedhar (Manipal University): There are several

advantages offered by FDCs. Many studies have shown that FDCs increase

both patient compliance and adherence. FDCs also simplify treatment

regimens. Physicians feel that it is convenient to prescribe FDCs rather

than single component products, and this sentiment is often shared by

patients. It is also generally believed that FDCs are cheaper and reduce

the costs of logistics, which is especially important when FDCs need to be

distributed to remote places.

PharmTech: Can you give examples of successful, rational FDCs?

Gupta (Imperial College London): Currently there

are numerous examples of success stories with FDCs. An FDC of

antituberculosis medications, compared with the corresponding

free-drug combinations, was associated with significantly higher

treatment rates and significantly lower adverse effects. Similarly,

among those with HIV, the use of an FDC of anti-HIV drugs has

shown greater rates of remission. In comparison to these examples,

A single dosage form that combines two or more active ingredients is known as a combination drug or fixed-dose combination (FDC). One

benefit of an FDC is that it reduces the number of pills that must be taken, which can lead to improved patient compliance. However, FDCs

have also been a topic of concern, mainly because of the perceived potential for increased adverse events. Pharmaceutical Technology

speaks with researchers to explore the benefits and concerns of FDCs, and some of the challenges involved in their formulation.

Participants include Dr. Ajay K. Gupta of International Center for Circulatory Research, Imperial College London; Dr. N. Udupa, professor

and principal at Manipal College of Pharmaceutical Sciences, Manipal University in India; and Dr. D. Sreedhar, assistant professor in the

Department of Pharmacy Management, Manipal College of Pharmaceutical Sciences, Manipal University in India.

Fixed-Dose Combinations


the success stories with the use of FDC in the field of cardiovascular

medicine are not that dramatic. However, there is a rapidly growing

body of data, suggesting that the usefulness of FDCs in cardiovascular

and metabolic medicine is likely to be no different than that seen in

other fields of medicine.

In cardiovascular medicine, the main utility of FDCs is mediated

through improved compliance, which in turn may increase the

treatment efficacy and decrease the outcomes. This hypothesis is

partially supported by findings of our meta-analyses: the use of FDCs

(compared with the use of corresponding free-drug combination) was

associated with a greater (albeit statistically insignificant) reduction.

Elsewhere, a few observational studies have shown that the improved

adherence with medications is likely to be associated with greater

cardiovascular benefits.

Another potential advantage with the use of FDC is a possible

reduction in adverse effects. In our meta-analysis, compared with the

corresponding free-drug combination given separately, allocation to FDC

was associated with lower adverse event rates. The use of a low-dose

FDC of two drugs as an initial therapy (in several situations) may have

significantly lower adverse events and a better tolerability, than either of

the medication alone. A classic example of this is an FDC combination of

an angiotensin-converting enzyme (ACE) inhibitor and a calcium-channel

blocker (CCB) is likely to be associated with lower incidence of ankle

swelling, compared with the same dose of CCB alone.

Udupa/Sreedhar (Manipal University): Fixed-dose

combinations are especially useful when treating diseases like human

immunodeficiency virus/acquired immunodeficiency syndrome (HIV/

AIDS), malaria, and tuberculosis where more than one drug is usually

recommended. There are also certain other conditions and diseases,

such as cancer, cardiovascular diseases, diabetes, neuropsychiatry

and pain where FDCs may offer benefits. Some successful and rational

FDCs include:

• Antiretroviral combinations: abacavir + lamivudine, tenofovir

disoproxil fumarate + emtricitabine and efavirenz + tenofovir +

emtricitabine.

• Antimalarial combinations: artesunate + amodiaquine, artemether +

lumefantrine and amodiaquine + sulphadoxine + pyrimethamine.

• Antitubercular combinations: Rifampicin + Isoniazid + Pyrazinamide.

• Hypertensive combinations that provide better blood pressure

control: Amlodepine + Atenolol, Amlodepine + Losatan and

Irbesartan + Hydrochlorthiazide.

• Antidiabetic combinations that provide better glycaemic control:

Glibenclamide + Metformin, Glipizide + Metformin and Pioglitazone

+ Metformin.

PharmTech: How do you think the benefits and disadvantages

of FDCs shape up against one another? Should the industry pay more

attention to potential FDCs or would the time be better spent on other

areas of innovation?

Gupta (Imperial College London): This is an interesting

question, but there is no readily available answer. In my opinion,

each new FDC formulation should be based on a thorough

understanding of disease mechanism, as well as the mechanism of

action, pharmacokinetics and pharmacodynamics of each constituent

component—separately and in combination.

There are a few FDCs that are more

frequently prescribed over the other because

of the prevalence of the clinical situations that

they are most effective in. However, given

the numerous clinical prescribing situations,

I believe all FDCs will have their own niche in

treatment settings. Having said that, I believe

that there are only a finite number of possible

FDCs and with the rapid introduction of new

FDCs, the market will probably be saturated in the next few years or

so. For long-term sustainability, the pharma industry should spend a

significant amount of time on other areas of innovation, including the

development of new drugs and effective drug delivery mechanisms.

Udupa/Sreedhar (Manipal University): Benefits and

disadvantages should be looked at simultaneously and not individually

when evaluating an FDC. If there is considerable evidence that the

proposed FDC has more benefits than disadvantages, then it’s a definite

‘go’ situation.

The pharma industry should definitely explore the potential benefits

FDCs offer over their individual component products. It is difficult for

small- to medium-scale companies to bear R&D costs and even larger

companies are finding it risky to develop new drugs and so most pharma

companies are now in search of new business models. One of these

options is to develop FDCs of existing individual components that are co-

prescribed in order to help preserve patents.

When developing FDCs, however, companies must consider the safety

and efficacy of the active components in combination, the benefits

of simultaneous use of active ingredients and possible interaction

between the components. Fixed-ratio combination products are usually

considered for marketing approval by regulatory authorities only when

the dosage of each ingredient meets the requirements of a defined

population group and when the combination has a proven advantage

over single compounds administered separately in its therapeutic

effects, safety, or compliance.

References

1. A.K. Gupta, S. Arshad and N.R. Poulter, Hypertension, 55(2), 399–407

(2010).

2. K. Jamerson et al., N Engl J Med., 359, 2417–2428 (2008).

3. ADVANCE, “ADVANCE Trial — Blood pressure lowering arm results”.

www.advance-trial.com

4. R.D. Feldman et al., presentation at Scientific Sessions 2007 of the

American Heart Association (Orlando, 2007). PT

“Many studies have shown that FDCs

increase both patient compliance and

adherence,” — Dr. N. Udupa and Dr. Sreedhar,

Manipal University

Tableting


10 mm penetration, which, in many cases, made them better suited for layered tablets. Granulation properties would be much the same as with non-layered tablets with the exception of reduced fines; good f low and compress-ibility are always desired.

Ethirajan (Tedor Pharma): It is beneficial if both layers have relatively equal physical properties, such as the amount of fines, bulk density and granulation properties. It is also ideal to maintain granule size less than one half of the layer thickness to achieve a clear scrape-off. Specifically, fines below 200 meshes can smear or coat the turntable surface and it may not be possible to achieve a clean scrape-off, which can lead to layer cross-contamination.

Cross-contamination

PharmTech: How can common formulation issues, such as the combination of incompatible products, be overcome?

Calvin (Elizabeth Companies): The incompatibility of multiple drug matrixes is often paramount in the decision of a new product design process. As mentioned, however, this issue can be overcome by keeping the matrices separated by an inert ‘barrier’ layer to prevent drug interaction.

Kirsch (Natoli): Incompatible APIs are the main driver for layered tablets. They enable incompatible ingredients to be administered in the same tablet without degrading the actives. As for excipient choice, this is why we have R&D; use what works.

Ethirajan (Tedor Pharma): Incompatibility between the tablet components can be overcome by having the in-compatible ingredients in different layers. It is critical to understand the physicochemical properties of the drug sub-stance, and preformulation compatibility studies will help identify such incompatibilities so that certain excipients can be avoided or be separated into different layers for bet-ter drug product stability. Multilayered technology is used in many instances to overcome incompatibilities between drug substances that need to be administered in a single dosage. Occasionally, in the case of three-layer tablets, a thin placebo layer may be used between the outer active layers to avoid incompatibilities.

Another vital part in developing multilayered tablets is excipient selection. It is preferable to use excipients that are compatible with the drug substances in both the layers to maximize drug product stability. Generally, scrapers

present in the multilayered machines are non-metallic in nature; hence, it is imperative that the use of abrasive excipients that may ruin these scrapers is avoided. Using excessive amounts of lubricants should also be avoided because these may interfere with adhesion between lay-ers. Excipient choices should also be based on the func-tionality of a particular layer (immediate release versus controlled release). PharmTech: How can layer cross contamination be avoided?

Behrens (IMA Kilian): Product losses can be very high when making layered tablets. Usually strong vacuum as-piration is used to clean the residual product on the die table after the dosage of each layer, thus preventing cross contamination. Over the years, vendors have developed several technical solutions that minimize the quantity of powder remaining on the die plate that needs to be re-moved by suction.

Calvin (Elizabeth Companies): Layer cross-contamina-tion can be avoided in a few different ways. For example, ensuring the feed frame is correctly adjusted and not leak-ing powder, properly adjusting the vacuum being applied to the front of the feedframe to keep the die table clean, and installing dies that are manufactured to the high limit on overall die height. Whenever the granulation characteristics and tablet size deem it necessary, a ‘Tail Over Die Scraper’ (a delrin cover that is held in place against the die table with spring steel to keep any granulation form slinging out of the die through centrifugal force) may be needed if any powder loss is incurred due to centrifugal force.

Kirsch (Natoli): Proper press set up is essential. Turret die tables have a certain amount of vertical run out. Often overlooked is the simple task of indicating a die table to locate the high point. Feeder clearance must be set at this point to achieve a minimal amount of clearance between the feeder and die table to reduce granulation loss. Scraper blades must be in good condition and free f loating on the die table to reduce cross contamination. Die tables must also be in excellent condition as any wear or damage will contribute to granulation crossover. Proper dust extrac-tion is also needed as presses suited for layered tablets generally have more and/or specifically designed vacuum nozzles. Again, reduced fines would be important. An-other crucial point is that skilled press set-up technicians and operators are a must.

Ethirajan (Tedor Pharma): Scraper and seal conditions of the feed frames are very important. It is also essential that excess granulation passing the scrape-off be vacuum cleaned so that fines from one layer don’t cross contami-nate the other. Reduced fill cams may be used to reduce the amount of granulation that needs to be scraped off from overfill of the die.

Control

PharmTech: How can the weight of individual layers be monitored and controlled accurately?

“It would be advisable to

invest in a purpose built

press engineered for layered

tablets,” —Doug Kirsch, Natoli.

Continued from Page s25


Behrens (IMA Kilian): When producing bilayer tab-lets, the in-line control of production, combining com-pression force measurement and statistical weight check are challenging for several reasons. If the compaction force for layer one is extremely low, it could be very dif-ficult to obtain a clear signal from the strain gauges. Low force compression rollers are available to help deal with this. The reduced mass ensures more accurate and reliable measurements. Another critical point is statistical sam-pling of the layers for weight checking. For sampling, the first layer has to be compressed at a higher force to achieve

enough hardness to make sampling and weighing possible. Some systems can achieve this by using specialized systems. For example, to avoid the production of second-layer-only tab-lets during layer one sampling, lower punches can remain in the up posi-tion while the fill-shoe for layer two is stopped.

Calvin (Elizabeth Companies):

Usually, two different process con-trol methods are employed to achieve this. The first, standard method is to utilize force control, which monitors the layer tamping pressure by means of a strain gauge transducer that, in turn, provides feedback to the press controller. This information is used to automatically adjust the meter-ing cam to keep the set pressure constant to maintain the correct weight and tamping pressure. The strain gauge should be sized so that it will be sensitive enough to ‘sense’ the lighter tamping pressures re-quired for producing a tablet layer

compared to the strain gauge that would be required for final tablet compression.

The secondary method is to select a multilayer tablet press that automatically collects sample tablets from each layer at regular intervals and then sends them to a weight testing unit, which would be included in the press control feedback loop, to provide in-process checks along with weight control.

Kirsch (Natoli): Tablet press manufacturers will be responsible for this through improved technology and engineering. By utilizing quality by design, the science of

“The incompat-

ibility of multiple

drug matrixes is

often paramount

in the decision

of a new product

design process,” — James Calvin,

Elizabeth Companies

Tableting


the formulation is understood and the design space can be exploited to deliver a controllable process. Controlled processes deliver a product with the required critical quality attributes that define what is to be delivered to the patient.

AestheticsPharmTech: Aesthetically, what consideration should be given to color?

Kirsch (Natoli): Aesthetics are always important to the consumer. However, as a manufacturer, the first concern would be, what the cost is and how well does it compress? Colors as well as flavors can affect tablet compression. Some may be more heat sensitive than others, resulting in picking or sticking issues. Others may have excessive fines resulting in punch and die binding, which increases tool and press wear.

A common error is developing a new product in R&D on a slow, partially tooled press and then submitting a New Drug Application before testing it on a production machine. The R&D press may not even have the same type tooling. If the product was developed on a ‘D’ tooling press and the production press was a ‘B’, dwell time would be reduced, resulting in poor layer cohesion or soft tablets. Partial sets of tooling will result in more time under pressure, therefore in-creasing tablet hardness. Again, poor layer cohesion and soft tablets could be an issue on a high-speed press. Production presses run at higher speeds and temperatures, increasing possible sticking, picking, laminating, and capping issues.

The criteria for color or f lavor choice should be what is least costly and runs best on a production press and not just what ‘looks pretty.’ There is a middle ground somewhere for marketing and production. Marketing will not have to deal with the production headaches. It may cost thousands or hundreds of thousands to do a trial on a production press, but would be more cost effective than wasting millions fighting it in full-scale production.

Ethirajan (Tedor Pharma): Colors play an important role in multilayered tablets. Firstly, it is a method of visual process control during compression. The extent of cross contamination, if any, can be easily seen when granulations of different colors are mixed during compression. When a color coating is not present, colored tablets also give a visual description to the drug product. In the case of over-the-counter products, color and aesthetics play a major role in consumer choice.

In-process controls and PATPharmTech: The pharma industry is paying increased atten-tion to in-process controls and process analytical technology (PAT). What are the challenges of applying these methodol-ogies to multilayer tablets over standard single layer tablets?

Behrens (IMA Kilian): PAT systems based on transmis-sion or reflection are seldom used on monolayer tablets. The amount of validation is high, and even more complex for bilayer or multilayers. It is also difficult to repeat the mea-suring results on each layer. The industry has to put more efforts into this issue.

Calvin (Elizabeth Companies): The only additional chal-lenge when pressing a multilayer tablet versus a standard tablet relates to process control to ensure that the prior layer is at the correct weight before allowing any automatic weight change to occur. The first layer must be in the correct weight range before any changes happen to the second layer. In the case of a three-layer tablet, the first and second layers must be in the correct weight range before allowing the third layer to make any weight adjustment.

Kirsch (Natoli): PAT is best used during development to understand the variables involved in achieving the formula-tion design for a quality tablet. Transferring the PAT meth-ods to manufacturing is necessary only when the informa-tion generated by the measurements is required to achieve the necessary process control to deliver the desired product. However, PAT measurements can provide information for feedback control, which can offer the manufacturer an op-portunity to move toward real-time release of a product. If traditional tablet press variables are properly controlled and a quality granulation is delivered to the tablet press, then the due diligence time spent in process development pays off with a robust manufacturing process that does not require process analytical instrumentation.

Ethirajan (Tedor Pharma): All controls that apply to a single layer tablet must be performed for each different layer in a multilayer tablet. For example, in a bilayer tablet, the granulations for each of the layers are manufactured sepa-rately. Both layers have a drug, and then both layers must be monitored and controlled for drug uniformity in the blend/granulation. During compression, in-process controls for weight must be used for both layers. Hardness for the first layer and hardness for the final tablet must also be moni-tored. If controlling the specification for one of the layers is more challenging, it also affects the formulation and scale-up of the entire process.

PharmTech: Batch yields for multilayer tablets can often be lower. What future improvements would help increase yields?

Behrens (IMA Kilian): Vendors have developed many new systems and machines that can help in this area. I believe that one important feature of such systems is user-friendly software. In addition, simple features that enable shorter set-up times can be beneficial.

“Excipient choices should

also be based on the func-

tionality of a particular layer,” — LakshmiDevi Ethirajan, Tedor Pharma


Calvin (Elizabeth Companies): I disagree; the batch yield is not affected by the reduced tableting speed, but it is reduced by several other factors. Operating a layer press is the same as operating several presses at the same time; for example, in the case of a three-layer press, you have three different powder feeders possibly containing three differ-ent granulations that can contribute to reduced yield. The feeders can contribute to the loss if care is not taken during set up, or if they are not properly adjusted to the die table and are allowed to leak powder. The second major contrib-uting factor to batch yield is the vacuum. If the vacuum applied to the die table to eliminate cross contamination is not correctly balanced, then granulation may actu-ally be vacuumed from the feedframe during operation.

In particular, tablet layer sam-pling can be one of the foremost contributors to batch yield loss. During tablet sampling, powder loss cannot be avoided because of the compressions that must be removed and discarded due to the ‘sampled’ layer that is missing during the col-lection process. Batch yields can be increased by simply taking the time to properly adjust the powder feeders to the die table, correctly balancing the vacuum and by collecting the minimum amount of layer samples needed for the in-process inspection requirement.

Kirsch (Natoli): Bilayer tableting speeds are reduced by at least 50% as double-sided presses function as single-sided presses due to the sec-ond layer. Layer cohesion issues, tablet hardness, cross contamina-tion, or other compression issues may result in a further slowing of the press. Press manufacturers are always researching ways to improve multilayer press efficiency. Layer sampling typically slows produc-tion. Fette has introduced several methods to reduce sampling de-lays and a ‘punches up’ option to eliminate second layer only tablets. Older layer presses discarded excess product whereas product recircula-tion of individual layers is now pos-sible, which greatly increases yields. Improved load cell resolution will more accurately control weight for individual layers allowing for higher

speeds. Presses are available with 100 or more stations of tooling which will certainly increase output. It would be advisable to invest in a purpose built press engineered for layered tablets. Retro-fitted or converted presses do not function as efficiently.

Ethirajan (Tedor Pharma): Production rate yields are generally lower. This is because a two- or three-sided ma-chine only makes a single tablet with each head revolution. Also, the need for vacuuming off the granulation that passes the scrape off after each fill station causes higher granula-tion loss relating to low batch yield. PT

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Tableting


There are several formulation and manufacturing challenges that need to be addressed when working with multilayer tablets, but

meeting regulatory expectations is crucial. Pharmaceutical Technology speaks with Vilayat A. Sayeed, PhD, director of the Division of

Chemistry III at the US Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Science, Office

of Generic Drugs, to find out more about critical formulation factors.

Key Formulation Factors

PharmTech: How have advances in

pharmaceutical manufacturing technology

influenced the development of multilayer

tablets?

Sayeed (FDA): Improvement in the

understanding of the material science

(physical, chemical, and mechanical) and

the engineering of the tableting machine

to control weight of individual layer/s, total

tablet weight, and compression factors

for the layers are responsible for the advancement in pharmaceutical

technology of the multilayer tablets.

PharmTech: What critical factors do manufacturers need to be aware

of when producing multilayer tablets?

Sayeed (FDA): Critical factors can be broadly divided into material

attributes and process parameters. Material attributes such as:

compatibility, compressibility, compactability, adhesion, tensile strength,

flow properties, porosity, density, layer relaxation during shelf-life and

storage and propensity for in-vitro and in-vivo delamination are some of

the factors a manufacturer must understand in producing a multilayer

tablet. The process parameters includes impact of lubricant in each

blend, tamping force for initial layer(s) compression, final compression

force for tableting, and press speed. Both of these factors have to be fully

understood for making a quality multilayer tablet.

PharmTech: Which regulations, in particular, are applicable to

determining these critical factors?

Sayeed (FDA): Regulations are written to address and capture the

safety, efficacy and quality concerns, regardless of how the product is

designed and manufactured. It is the responsibility of the sponsor to

study, understand, and establish controls in the process to ensure that

the manufacture of a drug product can provide the intended product

performance and clinical outcome over its shelf life. There are no specific

regulations for multilayer tablets or any other pharmaceutical dosage

form, but 21 CFR 314 and 21 CFR 320 address the various issues that should

be addressed in the submission.

PharmTech: How can manufacturers best use a quality-by-design

approach to support the development of a new multilayer tablet?

Sayeed (FDA): Quality by design can be used to

comprehensively put forth the understanding of the product

formulation (drug substance inherent properties, excipient

properties, and variability) and manufacturing process on product

performance. The design elements should be based on prior

knowledge, risk assessment,

and process controls in

achieving the multilayer tablet

of desired quality. To further

enhance the understanding

where applicable, the

manufacturer should conduct

design of experiment studies to

develop and identify critical to

quality attributes and process

parameters. This systematic

approach of building quality by having a mechanistic understanding

of variables and their impact on the manufacturing process and the

performance of the product with limited dependence on the end-

product testing should be the focus and the intended use of quality

by design.

PharmTech: Are there any other issues specific to multilayer tablets

that companies will need to address in regulatory submissions?

Sayeed (FDA): The knowledge gained by applying the scientific

principles and risk management tools during the pharmaceutical

development must be fully discussed and those functional

relationships that are linked to product performance must be clearly

presented in the regulatory submission. In addition to providing a

complete mechanistic understanding supported by data developed

through the application of scientific and quality risk management

tools, the applicant should also provide the relevance and justification

of the product design to the product performance and clinical

outcome. The established controls and specifications should be based

on the sound scientific principles, ICH and regulatory agency guidance,

and should be fully justified. PT

“The established controls and specifications

should be based on the sound scientific

principles, ICH and regulatory agency

guidance, and should be fully justified,”

— Vilayat A. Sayeed, FDA

FDA’s Vilayat A. Sayeed


A Q&A with Accu-BreakPharmaceutical Technology speaks with David Breach, a technical consultant for formulation development and

manufacturing at Accu-Break Pharmaceuticals.

Multilayer Technology

PharmTech: Accu-Break has used multilayer

technology in an innovative way, could you

please describe the reasoning behind the

drug-free layer?

Beach (Accu-Break): We have developed two distinct multilayer

tablet technologies, known as Accu-B and Accu-T, which incorporate a

drug-free layer. With the Accu-B technology, the dosage form has two

layers, one of which is drug-free. The second layer contains drug and is

deeply scored. The drug-free layer provides several unique features: first

and foremost, given the deep score in the drug layer, the drug-free layer

forms a backbone that gives the finished dosage form mechanical strength

to withstand packaging and shipping operations. Secondly, the drug-free

layer is the fracture plane for the Accu-B tablet. The tablet can be broken

through the score and the fracture occurs in the drug-free layer. Compared

with a conventionally scored tablet, the Accu-B bilayer design ensures

partial dosing accuracy and eliminates concerns over loss of mass. Using

the Accu-B technology, scored tablets can be made that would satisfy

the testing and data requirements for both the European Pharmacopeia’s

Monograph 0478 and the FDA’s recently proposed Guidance for Industry,

Tablet Scoring: Nomenclature, Labeling, and Data Evaluation.

Our Accu-T technology uses up to five layers in a taller-than-wide

tablet, and the incorporation of drug-free layers serve one of two

purposes:

• The drug-free layer provides a physical barrier between active

ingredients. This barrier allows the formulation of incompatible

actives with no worries about co-mixing and resultant physical or

chemical stability issues. The technology utilizes machinery that

can produce tablets with up to five compressed layers so the use of

more than one drug-free layer can facilitate a “poly pill” with three

different API-containing formulations.

• A drug-free breaking layer is incorporated into the middle of an

Accu-T tablet and can be used to separate the drug-containing

layers. Since the drug-containing layers are physically located

at the top and bottom of this taller-than-wide tablet, breaking

the tablet through the middle drug-free layer separates the dose

into exact halves. Unique fixed-dose combination (FDC) tablets

can be made where the top and bottom layers contain different

actives. In this configuration, the two different drug layers can be

separated if desired by splitting the tablet through the middle-

drug free layer. Patients taking antihypertensive FDCs can be

confronted with side effects that result from one of the drugs

within the FDC, resulting in prescription discontinuation. With

the Accu-T FDC tablet design, a patient could suspend treatment

with one of the drugs in the FDC by simply breaking the tablet

through the middle drug-free layer. When appropriate, the patient

could then resume taking the whole tablet, which allows some

dose flexibility without having to stop the prescription entirely.

The tablet could also be used to initiate treatment with a single

agent and then add the second and, thus, efficiently transitioning

the patient into a convenient FDC without the need for separate

prescriptions during the titration phase.

PharmTech: Does the use of a drug-free layer to separate incompatible

APIs require further consideration specific to the choice of excipient(s)?

Beach (Accu-Break): Excipient choices are broad and specific

requirements are not unique to the technology, meaning common

excipients are readily adaptable for use in Accu-Break technologies. For

Accu-B tablets, the requirement for a strong backbone in the drug free layer

necessitates the use of excipient materials with good compressibility (e.g.,

microcrystalline cellulose). Typical finished tablet hardnesses are more than

20 Kp. In addition, in an immediate release product, the desire to have the

drug free layer separate rapidly from the active containing layer typically

requires the use of higher levels of disintegrant in the drug-free layer.

PharmTech: Why have fixed-dose combination (FDC) drugs been

criticised in the past?

Beach (Accu-Break): The largest historical criticism of FDCs has

come from the lack of dose flexibility. Taking antihypertensive FDCs

as an example, treatment is typically initiated with a single agent,

which is titrated to a maximum tolerated dose. If the desired effect

on lowering blood pressure is not achieved, a second agent is added,

which also requires titration and can lead to lowering the dose of the

first agent. A third agent is sometimes added to the mix, or substituted

for one of the initial drugs. This process continues until the patient’s

blood pressure is within the target range, and then the physician looks

for an option to transition the patient to an FDC that contains APIs at

the effective dose for that patient. This is done of course to simplify the

dosing regimen for the patient in an attempt to maintain adherence

to the regimen. Problems arise when a dose adjustment is necessary

due to the inflexibility of traditional FDCs. The convenience of a single

dosage form is offset by the inability to manage dose adjustments

without the need for new prescriptions. If a patient is transitioned to

an FDC, inevitably an adjustment will be made to their dose(s), their

regimen, the specific drugs being used, or all of the above. So, from

that perspective, the criticism is justified. However, for those patients

who are effectively managed using FDCs, the ability to take lower doses

of two or more medications in a single dosage form is highly desired,

especially if it is a once-a-day regimen. PT

David Breach, Accu-Break


Anticounterfeiting

BackgroundFDA published in October 2011 the final guidance, Incor-poration of Physical- Chemical Identifiers (PCIDs) into Solid Oral Dosage Form Drug Products for Anticounterfeiting (1). The document was issued as a follow-up to the agency’s 2004 Counterfeit Drug Task Force Report to facilitate the use of authentication technologies such as PCIDs, and is meant to provide guidance for industry on how using the technology would change the information expected to be provided in regulatory submission (2). The use of a PCID, defined in the guidance as “a substance or combination of substances possessing a unique physical or chemical property that un-equivocally identifies and authenticates a drug product or dosage form,” is voluntary. PCIDs include inks, pigments, flavors, and molecular taggants.

In the guidance, FDA recommends that the PCID’s in-gredients be pharmacologically inactive so that they can be treated as excipients. To minimize toxicological risk, the agency recommends that drugmakers use permissible direct food additives, food substances that are generally recognized as safe (GRAS), or ingredients listed in the agency’s Inactive Ingredient Guide (IIG) that have been used in solid oral dosage forms.

To minimize the risk that a PCID will adversely affect the dosage form’s identity, strength, quality, purity, potency, or bioavailability, FDA recommends that companies add a PCID to the product at the lowest level that will ensure the dosage unit’s identification. PCIDs that are relatively inert also can minimize the potential for adverse interactions. In addition, the guidance states that manufacturers should ex-amine the potential effect of a PCID on the product’s qual-ity, performance, and stability.

In terms of documentation, the guidance includes rec-ommendations for new drug and abbreviated new drug applicants proposing to incorporate PCIDs into new solid oral dosage forms. The guidance also describes the docu-mentation recommended for applicants that want to incor-porate PCIDs into solid oral dosage forms as a postapproval change.

The amount of information to be provided for a PCID depends on its pharmacological characteristics, toxicologi-cal characteristics, and design, according to the guidance. Less information would be expected for a PCID that is a

Physical-Chemical IdentifiersA Q&A with FDA on the Final GuidanceModerated by Angie Drakulich

FDA answers key questions about the October

2011 guidance on using physicalÐchemical

identifiers in solid oral dosage products to help

prevent and avoid counterfeiting.

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Anticounterfeiting


permissible direct food additive, a food substance that is GRAS, or an ingredient listed in the IIG than for a novel PCID. According to the guidance, the agency would expect to see information about items such as the PCID’s chemi-cal composition, the rationale for selecting the PCID, how the PCID is integrated into the product, the location of the PCID in the product, and the relevant physical–chemical attributes of the PCID.

Pharmaceutical Technology asked the agency a few follow-up questions about the guidance and plans going forward. The responses are provided by an FDA Spokesperson.

PharmTech: Location and presence of a PCID in a solid dosage form is crucial in order to avoid interaction with the drug substance. What are the key concerns that manufacturers must consider in this regard (e.g., release rate, drug sub-stance interaction)?

FDA: The key concerns for the presence and location of a PCID in a solid oral dosage form are potential interactions with the drug substance and potential impact on the drug product release rate. Interactions with the drug substance could cause degradation. Interactions with rate-controlling exipients could impact the release rate of extended release or delayed release dosage forms.

PharmTech: It is recommended that industry use already ap-proved direct food additives (e.g., those listed in GRAS or IIG) at the lowest specified levels to avoid adverse reactions. Does the agency have plans to create a list of specific PCIDs for the pharmaceutical industry to be used in the future? Will PCIDs that are not in the GRAS or IIG be considered by the agency if submitted by an applicant for use?

FDA: The agency does not have plans to create a list of specific PCIDs for the pharmaceutical industry. Proposals for the use of PCIDs that are not in the GRAS or IIG lists can be submitted by an applicant for evaluation by FDA.

PharmTech: According to the guidance, “There are various available means for presentation and detection of PCIDs (e.g., photolithography, holography, optical microscopy,

laser scanning devices, excitation/fluorescence detection). Some identifying characteristics, such as pigments or f la-vors, could be easily observed by patients, healthcare prac-titioners, and pharmacists. Others could require the use of a detection instrument (e.g., a scanner, photometric detector, mass spectrometry).” What is the expectation in terms of who has responsibility—for example, healthcare providers or pharmacists—for determining and authenticating the presence of a PCID before patient distribution?

FDA: There is no intention by FDA to place a burden of re-sponsibility on healthcare providers to authenticate drugs by determining the presence of a PCID before patient dis-tribution.

PharmTech: Are there plans to extend the guidance beyond solid dosage forms?

FDA: There are no plans at this time to extend the guidance on PCIDs beyond solid oral dosage forms.

PharmTech: What other an-ticounterfeiting measures does FDA recommend for oral solid dosage forms in addition to PCIDs?

FDA: FDA encourages manufacturers to continue exploring promising technologies for use as anticounterfeiting mea-sures. These may include radiofrequency identification (RFID), nanotechnology, encryption and other track-and-trace technologies.

PharmTech: Manufacturers can submit information about their intent to use a PCID in a solid oral dosage product in an NDA or ANDA or as a postappoval change. Some industry members have raised convern over confidential-ity. Can you confirm that PCID information submitted in these documents is confidential and therefore protected from would-be counterfeiters?

FDA: FDA confirms that information on PCIDs submitted by applicants or master file holders is considered confidential.

Reference

1. FDA, Guidance for Industry: Incorporation of Physical- Chemical

Identifiers (PCIDs) into Solid Oral Dosage Form Drug Products

for Anticounterfeiting (Rockville, MD, October 2011).

2. FDA, Counterfeit Drug Task Force Report: “Combating Coun-

terfeit Drugs” (Rockville, MD, February 2004). PT

The key concerns for the presence and

location of a PCID in a solid oral dosage form

are potential interactions with the drug

substance and potential impact on the drug

product release rate.

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Excipient GMP

Between September 2010 and December 2011, a joint committee organized by NSF International worked to complete a draft of NSF 363, a new American National Standard for excipient GMP. The draft

standard, Good Manufacturing Practices (GMP) for Phar-maceutical Excipients, has completed the public comment period and a final version is to be balloted shortly (1). The new standard aims to establish industry-wide GMP require-ments for the manufacture of excipients.

NSF 363 was developed based on the joint International Pharmaceutical Excipient Council and the Pharmaceutical Quality Group (IPEC–PQG) Good Manufacturing Prac-tices Guide for Pharmaceutical Excipients (2). The sugges-tions expressed in the IPEC–PQG guide were reworked into requirements of the standard. Other IPEC guides are referenced in NSF 363 to clarify how industry can achieve conformance to the standard.

Background and importance of an excipient GMP standardNSF is an independent, not-for-profit, nongovernmental or-ganization and an Accredited Standards Developer of the American National Standard Institute (ANSI). ANSI is a private, nonprofit organization that administers and coor-dinates the US voluntary standardization and conformity assessment systems. ANSI is the US representative to the In-ternational Organization for Standardization (ISO). Ameri-can National Standards are developed in conformance with the ANSI Essential Requirements to ensure that standards are developed through participation by those directly and materially affected without financial or organizational membership barriers, a lack of dominance by a single in-terest category, individual, or organization, and a balance of interests (3).

Of relevance to the industry is the fact that the National Technology Transfer and Advancement Act of 1996 requires that federal agencies adopt private-sector standards, par-ticularly those developed by standards-developing organiza-tions, wherever possible, in lieu of creating proprietary, non-consensus standards. Further, the US Office of Management

The American National Standard for Excipient GMP Impact on the ManufacturerIrwin Silverstein

The author reviews significant changes to GMP for

excipients in the forthcoming American National

Standard, including a risk-based approach to

excipient manufacture, why new requirements

were proposed, and their potential impact to

excipient manufacturers.

Irwin Silverstein, PhD, is vice-president and chief operating

officer at International Pharmaceutical Excipients Auditing,

1655 N. Fort Myer Drive, Suite 700, Arlington, VA 22209,

tel. 703.351.5266.


and Budget’s Circular A119 provides for “Federal Participa-tion in the Development and Use of Voluntary Consensus Standards and in Conformity Assessment Activities.” As a result, FDA may adopt the ANSI standard GMP regulations for excipient ingredients manufactured for use in pharma-ceutical dosage forms intended for US domestic markets.

The NSF joint committee organized to prepare the excipi-ent GMP standard, designated as NSF 363, is comprised of representatives of excipient manufacturers, pharmaceutical users, and the general interests of the industry, including FDA, academia, and public health organizations. The final draft of NSF 363 was completed in the fourth quarter 2011

and was made available for public comment at the end of the year. The 45-day public comment period ended in January 2012, and the NSF joint committee reviewed the comments to the draft standard. Revisions to NSF 363 are in progress with final approval of the standard is expected to occur in the second quarter of 2012. Following the joint committee’s approval, the standard will be considered by NSF’s Council of Public Health Consultants with final approval by ANSI’s Board of Standards Review. If approved as expected, the standard will be published by the end of 2012.

New excipient GMP requirementsExcipients come from a broad range of the chemical- and food-ingredient industries. Inorganic excipients usually begin with the mining of minerals. Excipients whose start-ing material is grown on a farm or forest are often further processed into a derivative through chemical reaction or fermentation. Synthetic excipients can be produced at the manufacturing site from basic chemical starting materials, such as ethylene and acetylene. The one process common to all excipient manufacturing is purification of the material to meet the requirements of a pharmaceutical ingredient. A key challenge of the NSF joint committee, therefore, was to develop excipient GMPs that would be applicable to the diverse operational activities of the excipient industry.

Risk assessment. NSF 363 represents the evolution of the joint IPEC–PQG GMP for Pharmaceutical Excipients (2) into an American National Standard suitable for regulation by FDA. The most significant new requirement in NSF 363 not found in the joint IPEC–PQG guide involves the use of risk management to ensure consistent excipient quality. For

the purpose of the article, quality is taken to mean consis-tent excipient composition and freedom from contamina-tion. Risk assessment is defined in NSF 363 as “a systematic process of organizing information to support a risk decision to be made within a risk management process. It consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards” (1). (For details on conducting and documenting risk assessments as required by the standard, please see the article “Conducting Risk Assessment in Support of ANSI Excipient GMPs” in this issue.) The IPEC–PQG excipient GMP guide, as well as other IPEC guides, provide additional resources for risk assessment. The purpose of the many risk assessments stipu-lated in NSF 363 is to identify risks to excipient quality to assure control measures are commensurate with those risks (1). Several sections and clauses of the new standard are ex-plained below. Note that the term “Section” as used in this article refers to requirements that also contain enumerated subordinate requirements referred to herein as “Clauses.”

The first clause in NSF 363 to refer to risk is 4.2.1 (Quality Management System/ Documentation Requirements/Gen-eral) where the appropriate use of quality risk-management principles, defined as a systematic process for the assess-ment, control, communication, and review of risks to the quality of the excipient across its life cycle, are to be used to evaluate changes to the quality management system. Such changes include activities, operations, and processes that pose a risk to excipient quality. Also in this clause is the re-quirement to document a risk assessment that justifies those other clauses of the standard that do not apply to excipient manufacture and are thus not implemented.

Section 4.3 on Quality Management System/Change Con-trol requires the implementation of risk assessment as a tool to determine the impact of change involving the manufacture of the excipient. Here, IPEC–Americas has provided a guide as a basis for conducting the risk assessment. Any change that may impact the consistent composition or performance of the excipient should be considered potentially significant and the pharmaceutical customer should be notified as suggested in the IPEC guide for significant change reporting (4).

Section 6 on Resource Management requires several risk assessments to identify the potential for contamination of the excipient. For example:

• Clause 6.2.3 (Human Resources/Hygienic Practices)

describes risk assessment to identify the potential for contamination of the excipient by personnel and/or their activities. Where a risk to the excipient exists, the standard provides five measures that may be taken to minimize said risk. The proposed control measures will be familiar to manufacturers who have implemented excipient GMPs as noted in the IPEC–PQG guide (2).

• Clause 6.3.1 (Infrastructure/Buildings and Facilities)

requires risk assessment to evaluate the threat to ex-cipient contamination posed by the buildings and facili-ties. This assessment is to consider the intended use of

A key challenge was to develop

excipient GMPs that would

be applicable to the diverse

operational activities of the

excipient industry.

Excipient GMP


the excipient (i.e., oral, parenteral, topical applications, etc.). The five aspects presented for consideration are discussed in the IPEC–PQG guide (2). The provision to perform the risk assessment relative to the marketed intended use of the excipient links how the excipient is marketed to the tolerance for risk of contamination from the manufacturing facility.

• Clause 6.3.3 (Utilities) stipulates evaluation of contami-nation risk from utilities but does not require linkage to the intended use of the excipient.

• Section 6.4 on Work Environment requires the assess-ment of contamination risk from exposure to the work environment. This risk assessment is linked to customer requirements and marketed use. The standard notes five control measures that are to be considered when conducting this assessment for risk. The clauses under 6.4 require docu-mentation of conformance to the control measures imple-mented to address the risk to excipient quality noted in the assessment. However, Clause 6.4.4 (Pest Control) provides for a risk assessment to identify the elements needed in a pest control program.

Section 7 on Excipient Realization, further provides for risk assessments, as follows:

• Clause 7.4.1 (Purchasing/Purchasing Process) requires

the identification of quality-critical materials and ser-vices through risk assessment. The requirements of this clause are applicable only to those materials and ser-vices identified as quality-critical, except for the gen-eral expectation to have an agreed specification from approved suppliers. While neither the standard nor the IPEC–PQG Excipient GMP guide provide criteria for the determination as to whether a material or service is quality-critical, the assessment should be based on the potential impact to excipient quality (2). The suppliers of quality critical raw materials should be expected to notify the manufacturer of a process change so that the excipient manufacturer can evaluate the change for the potential impact to the excipient.

• Clause 7.5.5.1 (Production and Service Provision/Pres-ervation of Product/Raw Material Packaging Systems) requires a risk assessment to assure the storage and handling of raw materials provides suitable protection against deterioration or contamination and that iden-tification labels remain legible.

• Clause 7.5.5.2 (Production and Service Provision/Pres-ervation of Product/Excipient Packaging Systems) pro-vides for a risk assessment only where reusable contain-ers are returned for further use.

The only requirement for risk assessment in Section 8, Measurement, Analysis and Improvement, is in clause 8.3.2 (Control of Nonconforming Product/Reworking). Here, a risk assessment is required to assess the risk of the rework operation to excipient quality.

In conclusion, the provisions for risk assessment in NSF 363 are new in that they are to be formally conducted and

documented. Informal assessment of risk to excipient qual-ity has always been an expectation in IPEC excipient GMP guides however.

The provisions for risk

assessment in NSF 363 are

new in that they are to be

formally conducted and

documented.

Other noteworthy requirements. Several other provisions in NSF 363 are either new to excipient GMP requirements or differ from that suggested in the IPEC–PQG Excipient GMP guide (2). In particular, the excipient manufacturer should be aware of the following differences.

Clause 4.2.4 (Quality Management System/Documenta-tion Requirements/Control of Records) requires that records be kept for 1 year beyond the excipient expiration date or first re-evaluation date. The standard further states that where the manufacturer does not stipulate a re-evaluation or expiration date, the records should be retained for five years. The IPEC-PQG Excipient GMP guide merely suggests keeping records for a defined period.

Specified responsibilities of an independent Quality Unit are noted in Clause 5.5.1 (Management Responsibility/Re-sponsibility, Authority, and Communication/Responsibil-ity and Authority) with allowance to delegate some duties. While these responsibilities are also listed in the IPEC–PQG Excipient GMP guide as is allowance for delegation, the standard further notes that ultimate responsibility for oversight and approval remains with the Quality Unit.

As noted, Clause 7.4.1 (Purchasing Process) requires the identification of quality-critical materials and services. However, unlike the IPEC–PQG Excipient GMP guide, the standard specifically includes packaging materials. Also where the guide notes that periodic audits may be required, the standard notes the assessments are to be ongoing. The expectation of the standard is for the manufacturer to con-tinuously monitor the conformance of these suppliers to the purchasing agreement.

Clause 7.4.3 (Purchasing/Verification of Purchased Prod-uct) adds several new requirements:

• Justification for not sampling any incoming material

• Verification of the measurements reported on the sup-plier Certificate of Analysis (COA)

• Verification that the Certificate of Conformance for

packaging components references the current agreed specification.

Section 7.5 on Production and Service Provision, also contains several new provisions:


• Requirements for equipment and utensil cleaning and

sanitization are expanded under clause 7.5.1 (Control of Production and Service Provision). In addition to the expectations noted in the IPEC–PQG guide, the stan-dard requires the establishment of criteria to confirm cleaning effectiveness, requires chronological records of cleaning activities and identification of the cleaning status of equipment.

• There is a requirement to demonstrate ongoing evidence

of process capability under Clause 7.5.2 (Validation of Processes for Production and Service Provision).

• Clause 7.5.3 (Identification and Traceability) stipulates

documentation that defines identification and trace-ability for raw materials in continuous processing. The IPEC-PQG guide suggests using the time material was processed for traceability. This clause also requires that labeling include the manufacturing address or a refer-ence to the site of manufacture.

• Under Section 7.5.5 on Preservation of Product, the

manufacturer is expected to justify the handling and storage conditions for quality critical materials.

• Where excipient is shipped in bulk, there is to be a list of

restricted or allowed previous cargoes for non-dedicated bulk transport equipment according to Clause 7.5.5.3 (Excipient Delivery).

Section 7.6, Control of Monitoring and Measuring Equip-ment, describes the expectations for measuring and test de-vices used to make quality-critical measurements.

There are several new expectations under Section 8.2.4, Monitoring and Measurement of Product:

• Clause 8.2.4.1.1 (Laboratory Controls) adds the require-ment to provide documentation of sample preparation to show conformance with the test method. In addition there is a requirement to reference the test method. This documentation will facilitate the investigation of Out-of-Specification test results.

• Clause 8.2.4.1.2 (Laboratory Procedures) notes that re-agents and test solutions are to have expiration or re-standardization dates.

• Clause 8.2.4.5 (Certificate of Analysis) includes the pro-vision noted in the IPEC–Americas COA guide to in-clude the “manufacturer’s name and site of manufacture or reference to the site of manufacture” (5).

Section 8.3 on Control of Nonconforming Product, adds a couple of requirements:

• Nonconformance is to be investigated to identify the

root cause and potential impact to other batches or products.

• Under Clause 8.3.2 (Reworking) customers are to be

notified if they are provided with a reworked batch. Such material represents a potential significant change since routine processing was not followed.

The last addition of note is in Section 8.4 on Analysis of Data, which requires monitoring of nonconformance with this stan-dard and of supplier nonconformance are new requirements.

ConclusionThis article highlights the new requirements for excipient GMP as reflected in NSF 363. It expresses the opinion of the author as to what requirements in the draft ANSI excipient GMP standard differ from the IPEC–PQG Excipient GMP Guide. It is important to note that at the time this article was prepared, the public com-ment period for the standard had just been completed. Based upon input, requirements as described here may be modified. The reader is thus urged to review the requirements in the approved NSF 363 standard for applicability to their manufacturing operation. While certain new requirements are expressed in the standard, they ei-ther evolved from implied expectations in the excipient GMP guide or are enhancements resulting from the current business and regulatory climate. NSF 363 is organized in accordance with ISO 9001 but adds new clauses where appropriate. The organiza-tion of this American National Standard will facilitate submission of the standard to ISO for their adoption as a global standard.

References 1. NSF Joint Committee, Draft Good Manufacturing Practices (GMP)

for Pharmaceutical Excipients (2012).

2. IPEC–PQG, Joint IPEC–PQG Good Manufacturing Practices

Guide for Pharmaceutical Excipients (2006).

3. ANSI, Essential Requirements: Due Process Requirements for

American National Standards.

4. IPEC–Americas, Significant Change Guide for Bulk Pharmaceuti-

cal Excipients (2009).

5. IPEC–Americas, Certificate of Analysis Guide for Bulk Pharma-

ceutical Excipients (2000). PT

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Risk Assessment, Excipients

The forthcoming American National Standard for GMP for pharmaceutical excipients, NSF 363, utilizes quality risk-management principles to ensure that the implementation of this stan-

dard provides appropriate controls in manufacturing to produce excipients that are safe, of appropriate quality, and of consistent composition (1). (See “The American National Standard for Excipient GMP” in this issue for background details). The need to apply risk-management principles to excipient manufacture and use was born out of the challenge of defining a clear and auditable standard that can be applied across the vast diversity of excipient manufacturing processes, their raw-material sources, their chemical and physical properties, and their many end users in different types of drug products. Attempts to define requirements in such areas as personnel hy-giene, infrastructure, or work environment, inevitably lead to clauses that may be appropriate for one excipient but not for others (e.g., indoor operations versus outdoor multiacre facilities, multiuse facilities versus dedicated production lines).

The Joint International Pharmaceutical Excipient Council and Pharmaceutical Quality Group (IPEC–PQG) GMP Guide for Pharmaceutical Excipients was used to de-velop NSF 363 (2). The standard addresses the aforemen-tioned industry differences by discussing various points for consideration during excipient manufacture as well as calling for a risk assessment. The American National Standard Institute (ANSI) is expected to review and ap-prove NSF 363 this year. This article provides guidance for industry on how to comply with NSF 363 upon its pending approval, with a focus on risk assessment as part of excipient GMP.

The need for risk assessment NSF 363 requires risk assessments to support decisions and implement controls (see Tables I–IV). For example, Section 4.2.1 on Documentation requires incorporating quality

Standardized Excipient GMP Conducting a Risk Assessment

Dale Carter

This article provides guidance for industry on

how to comply with the pending American

National Standard on excipient GMP, with a

focus on risk assessment.

Dale Carter is chair of the International Pharmaceutical

Excipient Council of the Americas (IPEC–Americas).

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risk-management principles into changes to the quality-management system (1). The International Conference on Harmonization (ICH) Q9 Quality Risk Management guide-line, a reference document for NSF 363, gives two primary principles: “The evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient” and “the level of effort, formal-ity, and documentation of the quality risk management

process should be commensurate with the level of risk” (3).

These principles can help to frame a company’s thought process when con-ducting and documenting risk assess-ment by focusing the activity on the overall goal of protecting the patient. The principles direct the industry to use science when determining the sig-nificance “of the probability of occur-rence of harm and the severity of that harm” (1). It is also pointed out that not all risks are equal, and therefore, each documented risk assessment may or may not provide the same level of detail or supporting data.

NSF 363 adopts the same definition for risk assessment as found in ICH Q9, namely: “a systematic process of organizing information to support a risk decision to be made within a risk management process. It consists of the identification of hazards and the anal-ysis and evaluation of risks associated with exposure to those hazards” (3). In Q9, a hazard is a potential source of harm and harm is “damage to health, including the damage that can occur from loss of product quality or avail-ability” (3). This definition highlights the difference between risk assess-ment for excipients and hazard anal-ysis for food ingredients. In Hazard Analysis and Critical Control Points (HACCP) plans used throughout the food industry, the focus lies on pre-venting microbiological, chemical, or physical contamination that is reason-ably likely to cause illness or injury. No consideration is given to consis-tency of composition or functionality of the ingredient. Excipient manu-facturers must assess the impact of a change to excipient composition on its functionality and performance in the drug product, but only the user of the

excipient can adequately make this assessment. The excipi-ent manufacturer understands the range of variability, in chemical composition and physical properties, of its prod-uct and may communicate this to the user during quali-fication. The excipient manufacturer is expected to use risk assessment to prevent deviations in the stated range of variability. For this reason, the excipient manufacturer’s documentation of its product’s composition and variability

Table I: NSF 363 sections requiring a risk assessment (Ref 1).

Sect. # Title Requirement

4.2.1 dDocumentation

requirements, General

…a documented risk assessment that

defines and justifies when the as/if/where

applicable clauses in this standard are not

implemented

6.2.3 hygienic Practices

To protect excipients from contamination,

the organization shall conduct a risk

assessment to identify areas where the

excipient is at risk of contamination from

personnel and/or their activities.

6.3.1 Buildings and facilities

The organization shall conduct a risk

assessment based on the organization’s

expressed, intended use of the excipient

(see 7.2.3) to identify areas in which the

excipient is at risk of contamination or mix-

ups due to deficiencies in buildings and/or

facilities.

6.3.3 utilities


assessment considering the risk to

excipient quality from utilities (nitrogen,

compressed air, steam, etc.) used in the

production, storage, or transfer of materials.

6.4 Work Environment


assessment to identify areas in which the

excipient is at risk for contamination from

exposure to the work environment.

7.4.1 Purchasing Process

If an agreement cannot be obtained, a

risk assessment must be performed and a

written justification for continued use of the

supplier shall be available.

7.5.5.2Excipient Packaging

systems

Where reusable excipient containers are

returned, the organization shall undertake a

risk assessment and establish appropriate

controls for their further use.

8.3.2 reworking

reworking excipient is a change under

the provisions of change control in this

standard (see 4.3) and shall only be

conducted following a documented review

of risk to excipient quality that is approved

by the quality unit.



provides crucial information for conducting an adequate risk assessment. This information is also a requirement of NSF 363 Section 8.2.4.6 on Excipient Composition (1).

Documenting a risk assessmentRisk assessment consists of risk identif ication, risk analysis, and risk evaluation with the output forming

the basis for determining appro-priate risk control. The sections of NSF 363 requiring risk assessment preload the process by defining the scope or risk question, providing the nature of hazards to be considered, and pointing to risk controls that should be implemented. The docu-mentation necessary to demonstrate conformance to the standard should facilitate assessment of the results in terms of the risks to be controlled, the reasoning and facts leading to the conclusions, understanding the risks that were considered, and pro-vides evidence that competent people equipped with adequate information followed a process that ensured a complete assessment. The actual pro-cess for conducting a risk assessment may vary depending on the scope of the exercise but the documentation, except where risk are either obvious or cannot possibly exist, should in-clude (4):

• Objective and scope of assessment

• Team members and their support-ing qualifications (e.g., technical expertise and/or training in con-ducting risk assessment)

• Description, diagram, or f low

chart of what was included• Supporting references and infor-

mation relating to the assessment, including policies and procedures

• Assessment methodology

• Risk identification results

• Data, assumptions, and their

sources and validation• Risk analysis results and evaluation

• Risk criteria applied and justifi-cation

• Limitations, assumptions, and

justification of hypotheses• Critical assumptions and other fac-

tors which need to be monitored• Discussion of results

• Conclusions and recommendations or reference to result-ing controls.As with all records, this documentation should be

maintained and be available for audit as well as for use in periodic review of the assessment to ensure its continuing validity and suitability in the presence of new informa-tion. Including a summary and reference to the risk as-

Table II: NSF 363 sections requiring justification (Ref. 1).


4.2.2 d Quality manual…justification of the processing step from

which point this standard shall be applied

5.5.1responsibility and

Authority

The Quality unit may delegate some

aspects of these activities if justified as

appropriate, however, they shall retain

ultimate responsibility for oversight

and approval of all delegated activities,

applicable controls, and final decisions.

7.4.3Verification of Purchased

Product

The organization shall justify any material

not sampled prior to approval and release,

such as when the material is too hazardous

or toxic to sample and test.

7.5.1 bControl of Production and

service Provision

…equipment and utensil cleaning and

sanitization procedures justifying the

method and frequency of cleaning,

establishing criteria for determining

effectiveness, and requiring chronological

records of cleaning activities as noted

above; the cleaning status of equipment

shall be known,

7.5.5 Preservation of Product

The organization shall define and justify

the conditions for the handling and storage

of quality-critical materials (see 7.5.3) so

their identity, quality, and conformance to

specification are not affected within their

shelf life or re-evaluation period.

Table III: NSF 363 sections requiring decisions based on risk assessment (Ref. 1).


4.3 Change Control

The Quality unit shall approve any changes

that based on risk assessment may impact

the quality of the excipient.

5.5.3 Internal Communication

Based on risk assessment, top

management shall be notified in a timely

manner of events that affect excipient

quality and shall support appropriate

corrective and preventive actions, in

accordance with a documented procedure.


sessment reports in the quality manual helps describe the quality management system and aids in understanding the basis for controls included as part of the GMPs. To pre-vent the loss of a company’s knowledge base, training and familiarization with the content of the risk-assessment documents should be included as part of succession plan-ning, personnel development or job descriptions for key positions where appropriate.

Conducting a risk assessmentConducting and documenting a risk assessment of the manu-facturing process as directed in the NSF 363 Section 6 6.2.3 on Hygienic Practices, 6.3.1 on Buildings and Facilities, 6.3.3 on Utilities, and 6.4 on Work Environment can be combined

into a common exercise and risk- assessment report. The report may begin with a summary of the risk-assessment results and supporting arguments. The common supporting documentation would be included in the body or an appendix. Supporting documentation includes items such as a description of the product with back-ground information such as:

• Support for excipient stability

• Susceptibility for growth of mi-croorganism and other charac-teristics

• Product’s intended use

• Description of the process and

a f low diagram showing all unit operations, inputs, and recycle streams

• List of team members participat-ing in the risk assessment with a description of their qualifications to perform such a task.

A clear statement supporting the ex-cipients unique chemical and physical characteristics and any unique pro-cessing conditions or equipment will help justify the exclusion or inclusion of potential hazards. For example, a low pH can be used to justify the ab-sence for specific controls to prevent microbiological contamination.

Documentation should demon-strate that the risk assessments re-quired in NSF 363 Section 6 were performed for all unit operations. A matrix table can be included docu-menting the process f low, unit op-erations, and production and storage areas in rows with columns listing

potential hazards and the justification for suitable con-trols (or controls being unnecessary) to protect against such risks as: contamination from personnel and/or their activities; contamination or mix-ups due to deficiencies in buildings or facilities; deterioration of excipient qual-ity from contact with utilities; and contamination from exposure to the work environment. Reference to the sup-porting documentation (including a statement of how the process f low was verified for accuracy and inclusion of all operations) should accompany the table.

The risk-assessment process for determining signifi-cant change as a part of change control is discussed in the IPEC–Americas Significant Change Guide (5). A key point from this guide is that, “Any change by the manufacturer

Table IV: NSF 363 sections requiring risk controls as a result of risk assessment (Ref. 1).


6.4.1 Air handling

Where the risk assessment has identified

that an air handling system poses a

potential risk to excipient quality, the air

handling system shall be designed and

maintained to assure adequate protection

of the excipient.

6.4.2 Controlled Environment

Where the risk assessment has identified

the need for a controlled environment,

it shall be monitored to assure excipient

quality.

6.4.3Cleaning and sanitary

Conditions

Where the risk assessment (see 6.3.1)

has identified that clean and/or sanitary

conditions of the work environment are

necessary to protect excipient quality, the

organization shall document procedures

assigning responsibility for cleaning and/or

sanitation.

6.4.4 Pest ControlThe elements of the pest control program

shall be determined by risk assessment.

6.4.7Washing and Toilet

Facilities

Based on the results of the risk assessment

in 6.2.3, facilities for showering and/or

changing clothes shall be provided.

7.5.5.1raw material Packaging

systems

Where a risk assessment has demonstrated

that storage and handling of raw materials

may impact excipient quality, the

organization shall:

a) provide suitable protection against

deterioration, contamination with

foreign substances, chemical and/or

microbiological contamination, and

b) ensure that identification labels remain

legible.



of an excipient that [may] alter an excipient physical or chemical property outside the limits of normal variability, or that is likely to alter the excipient performance in the dosage form is considered significant.” The level of sig-nificance depends on the type of change and is evaluated according to seven criteria:

1. Will there be a change in the chemical properties of the excipient as a result of the change?

2. Will there be a change in the physical properties of the excipient as a result of the change?

3. Will there be a change in the impurity (composition) profile for the excipient as a result of the change?

4. Will there be a change in the functionality of the ex-cipient as a result of the change?

5. Where applicable, will the moisture level changed?6. Where applicable, will the bioburden changed?7. Will there be a change in the origin of any raw materi-

als or contact packaging?These criteria can be used in a change-control program

and should be referenced in the documentation to comply with NSF 363 Section 4.3 on Change Control.

The requirements to perform documented risk as-sessments in support of GMP controls are not entirely new. Section 8.3.2 of the IPEC–PQG GMP guide states

(2): “An activity that is not a normal part of the manu-facturing process (reworking) should only be conducted following a documented review of risk to excipient quality and approval by the quality unit. As appropriate, when performing the risk assessment, consideration should be given to…..”

The procedures and controls associated with the IPEC–PQG GMPs have always been the output of risk- assessment exercises. NSF 363 takes this concept fur-ther to justify the thought process used to support and document controls are. Such documentation facilitates better understanding of GMP controls across excipient manufacture.

References 1. NSF Joint Committee, Draft Good Manufacturing Practices

(GMP) for Pharmaceutical Excipients (2012).

2. IPEC–PQG, Joint IPEC–QG Good Manufacturing Practices

Guide for Pharmaceutical Excipients (2006).

3. ICH, Q9 Quality Risk Management (2006).

4. IEC/ISO 31010, Section 5.5, Risk Management–Risk Assessment

Techniques, 1.0 (2009-2011).

5. IPEC–Americas, Significant Change Guide for Bulk Pharmaceuti-

cal Excipients (2009). PT

Ad IndexCOMPANY PAGE

Asahi Kasei ....................................................................................................................................................................................................... 48

BASF Corporation .............................................................................................................................................................................................. 25

Capsugel .......................................................................................................................................................................................................... 19

Dow Polyglycols .................................................................................................................................................................................................. 5

DSM Pharmaceutical Inc...................................................................................................................................................................................... 9

Elizabeth Companies ........................................................................................................................................................................................ 15

Evonik Degussa Corporation ............................................................................................................................................................................. 47

Ferro Pfanstiehl Laboratories, Inc. .................................................................................................................................................................... 20

FOSS NIRSystems .............................................................................................................................................................................................. 31

Metrics, Inc. ........................................................................................................................................................................................................ 3

MPI Research ...................................................................................................................................................................................................... 2

Natoli ............................................................................................................................................................................................................... 35

Pfizer CentreSource .......................................................................................................................................................................................... 17

Ropack ............................................................................................................................................................................................................. 21

Sheffield .......................................................................................................................................................................................................... 11

Spectrum Chemical ........................................................................................................................................................................................... 29

Thomas Engineering ......................................................................................................................................................................................... 23

ASAHI KASEI AMERICA, INC.

535 Madison Avenue, 33rd Floor

New York, NY 10022, USA

P (212) 371-9900 Ext. 217

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