Solid Dosage and Excipients

Supplement to the March 2012 Issue of 2012
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SOLID DOSAGE AND EXCIPIENTS 2012
Solubility
s6 Meeting Solubility Challenges

EDITORIAL
Editorial Director Angie Drakulich adrakulich@advanstar.com Patricia Van Arnum
Executive Editor Patricia Van Arnum pvanarnum@advanstar.com
Managing Editor Susan Haigney shaigney@advanstar.com formulation
Editor (Europe) Rich Whitworth rwhitworth@advanstar.com
Scientific Editor Amy Ritter aritter@advanstar.com s10 Advances in Taste-masking
Community Manager Stephanie Sutton ssutton@advanstar.com
Associate Editor Christopher Allen callen@advanstar.com Summary of BASF Webcast
Director of Content Peter Houston phouston@advanstar.com
Art Director Dan Ward powder technology
Washington Editor Jill Wechsler jwechsler@advanstar.com
Contributing Editors Jim Miller info@pharmsource.com; Hallie Forcinio editorhal@cs.com; s12 Powder Testing Techniques
Susan J. Schniepp sue.schniepp@mac.com; Lynn D. Torbeck lynn@torbeck.org;
and Eric Langer info@bioplanassociates.com
for Tablet Manufacture
Correspondents Hellen Berger (Latin/South America, hellen.berger@terra.com.br), Tim Freeman and Jamie Clayton
Sean Milmo (Europe, smilmo@btconnect.com), and Jane Wan (Asia, wanjane@live.com.sg)
All color separations, proofs, and film are produced by
continuouS proceSSing
Advanstar’s Scanning and Digital Prepress departments.
485 Route One South, Building F, First Floor, Iselin, NJ 08830, USA s18 Continuous Processing in
Tel. 732.596.0276, Fax 732.647.1235, PharmTech.com Solid Dosage Manufacturing
SALES Patricia Van Arnum
Publisher Mike Tracey mtracey@advanstar.com
Director of Sales Paul Milazzo pmilazzo@advanstar.com tableting
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Mid-West Sales Manager Irene Onesto ionesto@advanstar.com
Display, Web, Classified, and Recruitment Representative Tod McCloskey tmccloskey@advanstar.com
s22 Multilayer Tablets:
Executive Assistant Barbara Sefchick bsefchick@advanstar.com Key Challenges and Trends
An Industry Rountable featuring IMA Kilian, Elizabeth
Vice President Sales/Group Publisher Russ Pratt rpratt@advanstar.com Companies, Natoli Engineering, and Tedor Pharma
Sr. Production Manager Karen Lenzen, International Licensing Maureen
Cannon mcannon@advanstar.com, tel. 440.891.2742 or toll-free 800.225.4569
anticounterfeiting
ext 2742, fax. 440.756.5255, Audience Development Manager Melissa Feiro
s34 Physical-Chemical Identifiers:
A Q&A with FDA on the Final Guidance
Moderated by Angie Drakulich
Joe Loggia, Chief Executive Officer Tom Ehardt, Executive Vice President, Chief Administrative excipient gmp
Officer Steve Sturm, Executive Vice President, Chief Marketing Officer Ted Alpert, Executive Vice
President, Finance and Chief Financial Officer Andrew Pollard, President Georgiann Decenzo, s38 The American National
Executive Vice President Chris Demoulin, Executive Vice President Danny Phillips, Executive Vice Standard for Excipient GMP
President Ron Wall, Executive Vice President Eric Lisman, Executive Vice President Francis Heid,
Vice President, Media Operations Ward D. Hewins, Vice President, General Counsel Nancy Nugent,
Irwin Silverstein
Vice President, Human Resources J Vaughn, Chief Information Officer
riSk aSSeSSment
Pharmaceutical Technology does not verify any claims or other information appearing in any of
the advertisements contained in the publication and cannot take any responsibility for any losses s42 Standardized Excipient GMP
or other damages incurred by readers in reliance on such content. Pharmaceutical Technology Dale Carter
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s46 Ad Index
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Solubility
Meeting Solubility Challenges

Patricia Van Arnum
T
he solubility of an API plays a crucial role in drug dis-
MedioiMages/Photodisc/getty iMages
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
As drug-discovery and high-throughput screening and production and lead to poor patient compliance because
methods increase the diversity and number of of the higher doses required to achieve a therapeutic effect (1).
potential lead drug candidates, formulation As pharmaceutical companies attempt to resolve these issues,
scientists are tasked with the challenges of contract-service providers and excipient suppliers are seeking
to meet these challenges through targeted offerings.
addressing the problem of poorly water-soluble
drugs. Pharmaceutical companies, equipment Strategies for improving solubility
providers, contract-service providers, and Both physical and chemical methods can be used to improve
excipient manufacturers apply various approaches drug solubility, Chemical methods to improve solubility in-
for improving solubility. The article examines clude developing more soluble prodrugs or improving solubil-
some recent developments. 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
s6 Pharmaceutical Technology Solid doSage & excipientS 2012 P h a r mTe c h . c o m
be used in solid dispersions. These include methylacrylate interactions, the specific possible hydrogen-bonding in-
polymers, polyvinyl acetate, polyvinylpyrrolidone, copo- teractions are investigated at a molecular level to derive a
vidone, poly-(ethylene-vinylacetate-vinylcaprolatam), and quantitative expectation in terms of drug–excipient mis-
cellulose derivatives (e.g., hypromellose acetate succinate, cibility in a binary system. In this quantitative assessment,
hydroxypropyl methyl cellulose, hydroxypropyl cellulose, additional specific hydrogen-bonding capability is consid-
ethyl cellulose, and methyl cellulose) (1). ered. This involves considering polymers from a monomer
perspective (i.e., meaning the composition of the polymer)
Hot-melt extrusion and specifying the type of hydrogen bonding that could
Hot-melt extrusion is used to disperse APIs in a matrix at be involved and its impact on the solubility parameters.
the molecular level to form solid solutions and is used as Solubility-parameter estimation and molecular-interaction
a method to improve solubility of poorly water-soluble considerations are important tools in estimating first for-
drugs (3). Evonik has developed a system, Melt Extru- mulations in solid-dispersion product. High-throughput
sion Modeling and Formulation Information System screening is accomplished based upon molecular structure,
(MEMFIS), as a predictive modeling tool in developing hot- intra- and inter-molecular bonding, and their impact on
melt extrusion formulations. MEMFIS helps in selecting solubility parameters (1). In addition to MEMFIS, Evonik
initial formulations with no API consumption, using math- is positioned in solid-dispersions through its methylacry-
ematical models and algorithms based on solubility param- late polymers (Eudragit). Several late-stage products have
eter theories (i.e., hydrogen bonding and polar and dispersive been developed with these excipients in solid-solution for-
forces). MEMFIS uses chemical structures, solubility param- mulations. Evonik has both hot-melt extrusion and spray-
eters, physicochemical properties, and a myriad of process- drying capabilities.
ing conditions to suggest initial formulation components and Other companies are advancing their hot-melt extrusion
process settings for a hot-melt extrusion formulation (1). capabilities. In October 2011, Ashland Specialty Ingredients,
In terms of miscibility estimation, for example, MEMFIS which acquired International Specialty Products (ISP) in
evaluates which excipients have higher potential to form a 2011, announced it was adding a GMP hot-melt extruder at
solid solution by assessing the drug miscibility of a given its Columbia, Maryland, R&D center to better serve phar-
excipient in comparison to other excipients. The qualitative maceutical companies working with poorly soluble drug
method, (i.e., which excludes hydrogen-bonding capabil- compounds. The 180-mm Leistritz extruder allows com-
ity in the evaluation) considers the drug miscibility with panies that seek to commercialize drugs, which are made
an excipient in comparison to other excipients to make more soluble with dispersions from Ashland, to scale up to
the determination of whether one excipient is more or GMP clinical and commercial quantities produced by hot-
less miscible. Only dispersive interactions are considered. melt extrusion. Ashland planned to finish installing and
Qualitative-only methods may lead to the exclusion of valu- testing the equipment in the fourth quarter of 2011 and to
able excipients from the screening studies that could poten- begin a full-service offering early in 2012. The company has
tially form strong hydrogen bonds with the APIs (1). an existing extruder at its Wilmington, Delaware Research
In the quantitative evaluation in the MEMFIS, which Center. With the addition of the extruder, Ashland is able
is a deeper analysis, in addition to polar and dispersive 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 comparing the bioequivalence of Zuplenz 8 mg to Zofran ODT (orally dissolving
used in over-the-counter products, this dosage form in prescription drug tablet) 8 mg. The pharmacokinetic results of these studies demonstrated
products has been limited. Several companies are seeking to advance thin- that a single dose of Zuplenz, taken with or without water and under fed
films in prescription products. and fasting conditions, was comparable to Zofran ODT. In June 2008, Strativa
In August 2011, the specialty pharmaceutical company MonoSol Rx and MonoSol Rx entered into an exclusive licensing agreement under which
announced plans to develop a second oral film product, KP 415, a prodrug Strativa acquired the US commercialization rights to Zuplenz oral soluble film.
of methylphenidate, a commonly used medication for treating attention In January 2012, MonoSol Rx formed a joint venture with Midatech,
deficit disorder. MonoSol Rx is partnered with the biopharmaceutical a company developing nanomedicines, which is focusing on the
company KemPharma on the project. MonoSol Rx’s PharmFilm technology is commercialization, through partnering or licensing, of products that have
used to deliver drugs in lingual, sublingual, and buccal dissolving films combined the intellectual property of the companies’ respective technologies
MonoSol Rx partnered with Strativa Pharmaceuticals, the proprietary for the primary treatment of diabetes. The companies recently reported that
products arm of Par Pharmaceuticals, to develop an oral soluble film for they are conducting a Phase I clinical study of their most advanced candidate
Zuplenz (ondansetron), a drug to treat nausea and vomiting associated with that uses insulin-passivated gold glyconanoparticles (i.e., MidaForm insulin)
chemotherapy and radiation. The drug, approved by FDA in 2010, was the formulated into PharmFilm for buccal delivery. In November 2011, Midatech
first soluble film approved by FDA as a prescription medication, according received regulatory approval for a first-in-human study of MidaForm insulin
to MonoSol Rx. The FDA approval was granted based on clinical-study data delivered transbuccally. Phase I results are expected in the first half of 2012.
Pharmaceutical Technology Solid doSage & excipientS 2012 s7

Solubility
using both spray drying and hot-melt extrusion techniques Cellulosics offers several expicients for hot-melt extrusion
to determine the best solubility solution in clinical trials. applications, including poly (ethylene) oxide resins (e.g.,
In October 2009, ISP launched a drug-solubility initiative Polyox) and cellulosic derivatives [e.g., Ethocel (ethylcellu-
that focused on solubilization technologies that involved lose ethers)] and Methocel (cellulose ethers).
excipients, formulation, and related processing services, In April 2011, the CDMO Pharmatek Laboratories added
which included solid-dispersion technology, both hot-melt spray drying to its drug formulation and manufacturing
extrusion and spray drying. In 2009, ISP partnered with the capabilities. The company purchased a Buchi B-290 Mini
equipment manufacturer Coperion for advancing hot-melt Spray Dryer for formulation feasibility studies and small-
extrusion technology. scale clinical manufacture.
In February 2012, the CDMO Bend Research formed a
licensing agreement with Eli Lilly under which Lilly gains Academic research
access to Bend’s proprietary spray-dried dispersion technol- Researchers at Purdue University recently reported on an
ogy, which is designed to improve the bioavailability of com- extrusion-based approach where the dissolution rate of
pounds with low aqueous solubility. In addition, as part of poorly soluble drugs (griseofulvin, phenytoin, and spirono-
an already existing agreement with Lilly, Bend Research will lactone) was improved through solid crystal suspensions.
continue to provide formulation, development, analytical, The drug and mannitol were coprocessed in a hot-melt ex-
engineering, and manufacturing services to Lilly to support trusion operation. The resulting product was a mixture of
its preclinical and clinical development programs. In August the crystalline drug and crystalline excipient, with up to
2011. Bend Research also formed a collaboration with the 50% (w/w) drug load. The in vitro drug release from the
CDMO Xcelience for oral solid-solubilization formulation obtained solid crystalline suspensions was more than two
solutions and clinical-supply manufacture. orders of magnitude faster than that of the pure drug. The
In July 2011, the CDMO Pharmaceutics International (Pii) researchers reported that because the resulting product
added hot-melt extrusion to its formulation and process- was crystalline, the accelerated dissolution rate did have
development solutions capabilites. The company purchased the physical stability concerns as with amorphous formu-
a 16-mm and an 18-mm Leistritz twin-screw extruders. This lations. The researchers reported this approach is useful in
investment enables Pii to carry out feasibility studies to situations where the drug is not a good glass former or in
pilot-scale cGMP productionfor Phase I and II clinical-trial cases where it is difficult to stabilize the amorphous drug (4).
materials using hot-melt extrusion.
In 2009, BASF launched its polymeric solubilizer, So- References
luplus, which is used in hot-melt extrusion applications. 1. P. Van Arnum, Pharm. Technol. 35 (10), 50–56 (2010).
In 2010, the company partnered with GEA Niro to allow 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
BASF to make cGMP spray-drying tests and pilot produc- (2011).
tions of APIs at GEA’s test station in Copenhagen. Dow Wolf 4. M. Thommers et al., Mol. Pharmaceutics 8 (3), 727–735 (2011). PT
Emerging technologies: oral peptide delivery

Several characteristics of peptides limit oral bioavailability. These molecules parathyroid hormone (PTH) analog for the treatment of osteoporosis in
are relatively large in size. The hydrophilic nature of peptides limits the postmenopausal women completed a Phase II study in 2011. In November
absorption of these molecule in the gastrointestinal tract, and peptides are 2011, Unigene announced positive top-line results of its Phase II clinical
susceptible to degradation by enzymes in the stomach and intestine (1). To study evaluating an experimental oral PTH analog for the treatment
address these problems, Unigene Laboratories, a company involved in the of osteoporosis in 93 postmenopausal women. The study achieved its
design, development, and manufacture of peptides, has developed an oral primary endpoint with statistical significance and was conducted by
peptide delivery platform. Unigene as part of now terminated agreements with GlaxoSmithKline
The company’s technology platform, Enteripep, involves the use of (GSK). In December 2011, GSK returned the rights to the drug to Unigene.
an enteric coating to permit passage through the stomach into the Unigene, which is seeking a new licensing partner for the drug, sees
small intestine. An organic acid inhibits proteases, and an absorption the oral form of PTH as an alternative to injectable-delivered PHT. The
enhancer facilitates the uptake of the peptide by a paracellular transport PTH injectable market alone represents approximately $1 billion with
mechanism. Absolute bioavailability ranging from 1% to greater than sales expected to double over the next two to three years, according to
20% can be achieved (2). estimates from Unigene.
In 2011, Unigene had two late-stage oral peptide programs successfully Sources
advance in the clinic. Ostora, the company’s oral calcitonin licensed 1. Unigene, ÒProprietary Drug Delivery,Ó company information, www.
unigene.com/proprietary-delivery-technologies/, accessed Feb. 13, 2013.
to Tarsa Therapeutics, successfully completed a Phase III study. The 2. N. Mehta, presentation at the 6th Annual Obesity and Diabetes Drug
company expects to submit a new drug application by the end of Development Summit (Arlington, VA, July 20Ð21, 2010).
2012. The company’s oral formulation of a recombinantly produced

Quality
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generations to come. This mission is supported by sustainability as
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Its philosophies and metrics are evident in everything we do, highlighted by a
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only a responsible approach, but a strategic business driver.
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Formulation
Advances in Taste-masking
Patricia Van Arnum
Taste-masking of solid cifically soluble in gastric juice. These properties allow for
dosage and liquid drugs effective protection from unpleasant taste in the patient’s
Design Pics/Ron nickel/getty images
is a challenge for pharma- mouth and rapid release and onset of active ingredient
ceutical manufacturers. action in the stomach.
Most APIs are unpleasant In October 2011, BASF and Colorcon announced a
or harsh tasting leading to collaboration for the development of future film-coating
patient noncompliance. systems using BASF’s Kollicoat Smartseal 30 D and a new
This challenge affects all Colorcon preformulated additive. Colorcon developed
age groups, but is specifi- the preformulated additive system for use with Kollicoat
cally problematic for pedi- Smartseal 30 D to enable efficient preparation and ap-
atric patients. The global plication of this polymer in taste-masking applications.
market for pediatric drugs The preformulated additive lowers the number of materi-
and vaccines is forecast to reach $85 billion by year 2017, als to be dispensed by 50% and reduces the preparation
according to data from Global Industry Analysts. The US time by almost 40%, according to an Oct. 21, 2011, BASF
is the largest market for pediatric drugs followed by West- press release.
ern Europe. Implementing taste-masking programs into
the drug-manufacturing process is crucial to avoid losses
due to noncompliance. Pharmaceutical manufacturers are Taste-masking is an
faced with challenges in life-cycle management, cost con-
trol, global regulations, and patent protection. important consideration to
In a recent editorial webcast, Pharmaceutical Technol-
ogy examined formulation-development strategies in
ensure patient compliance.
product life-cycle management, including specialized for-
mulations such as pediatric formulations, and the specific “We have chosen Kollicoat Smartseal 30 D because it is
technical issues that may evolve in excipient selection and the best-in-class reverse enteric polymer for taste mask-
functionality, including taste-masking and moisture pro- ing”, said Kamlesh Oza, general manager, film coating at
tection, to develop an orally palatable product. Colorcon, in the BASF press release. “Kollicoat Smarts-
Participating in the webcast were: Avinash Thom- eal 30 D is the first water-based dispersion having both
bre, PhD, research fellow, pharmaceutical sciences with taste-masking and moisture-barrier properties. It was de-
Pfizer Global Research and Development, who discussed veloped to simplify and accelerate aqueous film coating
life-cycle management and new dosage form options; operations and opens new doors for formulating tablet,
Karen C. Thompson, PhD, distinguished senior inves- pellet, and particle coatings. Our collaboration to develop
tigator, pharmaceutical sciences at Merck & Co., who the additive will bring batch-to-batch color consistency,
discussed insight into pediatric formulations and re- performance, speed, and simplicity, enabling easy recon-
lated dosage forms; and Nigel Langley, PhD, MBA, head stituting of the film former in pharmaceutical coating
of North American technical sales, Pharma Ingredients operations while maintaining functionality,” he said.
& Services, BASF, who discussed novel taste-masking Kollicoat Smartseal 30 D is part of BASF’s existing
excipient solutions. The webcast may be found at www. tablet coatings portfolio. Under the Kollicoat brand,
PharmTech.com/Webcasts, see Taste-masking in Formu- BASF markets a range of coating polymers and copoly-
lation Development. mers that are used to coat tablets, capsules, and pellets
In 2011, BASF launched Kollicoat Smartseal 30 D, an and to control the release of drugs from solid-dosage
aqueous disperson of a film-forming polymer with taste- forms. The Kollicoat family includes: Kollicoat IR and
masking and moisture-barrier applications. The excipient Kollicoat Protect instant-release coatings, Kollicoat IR
is highly impermeable to water vapor, which helps pre- Color Coating Systems, Kollicoat MAE enteric coatings,
serve the potency of sensitive active ingredients, according Kollicoat SR 30 D sustained-release coatings, and the new
to the company. The polymer is stable in saliva and spe- Kollicoat Smartseal 30 D protective coatings. PT

Powder Technology
Powder Testing Techniques

for Tablet Manufacture
Tim Freeman and Jamie Clayton
I
Drugs in solid dosage form continue to be n tablets, the active pharmaceutical ingredient (API) is
universally popular, with the majority of often only a tiny proportion of the finished product. The
steps that precede the tablet press are designed to incor-
pharmaceutical actives still delivered as tablets.
porate the API within a blend that processes efficiently
Successful tablet manufacture relies on filling a to produce tablets of the required quality. Excipients include
die with a uniform, loosely packed blend and then fillers, as well as components that play a more active role in
compressing that powder to form a consistent, processing, such as glidants to improve powder flow and
stable product. A greater understanding of the lubricants that reduce ejection force and prevent adherence
powder properties that relate to performance in to the press.
These raw ingredients may be screened, granulated, dried,
the press and which upstream processes influence
milled, classified and blended, often in a number of steps, to
powder properties enables improvements to produce feed for the tablet press. Batch processing, in which
be made at the appropriate processing stage(s), a defined amount of material is processed and then tested to
leads to improved throughput, and enhances confirm its suitability for the next step, is common.
the quality of the finished product. This article Each ingredient and unit operation is a potential source
considers the different conditions to which the of variability arising from any number of factors including:
• Raw materials
powder is subjected in the tableting process,
• Human intervention (especially if the plant is manually
and discusses which powder properties should controlled)
be measured to accurately reflect likely powder • Sampling and analytical test method variability
behavior in the process. • 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
ALL FiGUreS Are CoUrTeSy oF AUThorS
able to detect a problem. This means that a specification

used to define acceptability—in a feed or after a process-
Tim Freeman* is managing director and Jamie Clayton ing step— must reliably identify a material that will fail to
is operations manager at Freeman Technology, 1 Miller process as required in a subsequent step or that will go on
Court, Severn Drive, Tewkesbury, Gloucestershire, to produce a substandard product. Such specifications must
GL20 8DN, United Kingdom, tel. +44(0)1684.851.551,
be based on properties that closely correlate with the aspects
fax. +44(0)1684.851.552, info@freemantech.co.uk, www.
freemantech.co.uk of performance that are critical to success. This approach
relies on identifying and measuring powder properties that
*To whom all correspondence should be addressed. have a defining influence on the efficiency of the operation
and the quality of the final product.
Figure 1: More permeable powders tend to flow consistently that varies at a relatively high frequency. The tablet press
from a hopper, while those that are less permeable can give weight control system cannot adequately compensate, which
rise to a low rate, ‘pulsing’ flow that is detrimental to process results in variable tablet weight. In contrast, more perme-
efficiency and product quality. able blends tend to exhibit more consistent flow, ultimately
delivering a more uniform density to the feed frame and a
High Permeability
Low Permeability 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
Fully de- paddles of the frame rotate. Agglomeration and attrition are
aerated
(max
both potential problems, exacerbated by the need to recycle
consolidation)
powder around this part of the process. Both can lead to seg-
regation of the blend, giving rise to non-uniformity in the
aerating finished tablet. Attrition additionally gives rise to dusting,
creating fines that can compromise processing efficiency
Fully aerated (fluidized) and the properties of the finished tablet.
In the feed frame, the powder flows under gravity but,
High & Consistent
Flow Rate
Low & ‘Pulsing’ depending on the design of the paddles, there may also be a
Flow Rate
significant element of “forced flow.” Angling the sweeping
paddles can help to force the powder down into the dies to
Analyzing the tableting process improve filling efficiency. While optimizing the flow regime
Powder behavior is influenced by an array of different vari- in the feed frame improves consistency and the rate of die
ables, including primary parameters such as particle size filling, doing so relies on understanding how the powder
and shape, as well as system factors such as extent of con- flows under different conditions and, in particular, the ma-
solidation and aeration. This complexity makes it difficult terial’s response to forcing conditions.
to predict behavior. To develop a secure basis for process op- In addition, the response of the powder to air is critical
timization, it is necessary to select powder property charac- for consistent die filling. A permeable blend that quickly re-
terization techniques that simulate the process environment, leases entrained air will settle rapidly and efficiently fill the
because it is difficult to reliably infer performance from test die. Simultaneously, air can provide lubrication and promote
data acquired under conditions that are not representative
of those applied during processing.
Manufacturing tablets from a blend tends to be a single Specifications must be
integrated process. However, closer analysis reveals four dis-
tinct stages, particularly in terms of the conditions applied based on properties that
to the powder. These are:
• Discharge from the feed hopper
correlate with critical
• Flow into and through the feed frame performance aspects.
• Die filling
• Compression, followed by ejection.
Hopper discharge. Tablet manufacture begins with dis- flow in the feed frame. Therefore, a material that releases air
charge of the blend from the hopper, ideally at a consistent, too easily may not flow consistently. Understanding exactly
controlled flow rate. Material flows under gravity, at rela- how the powder responds to air can be critical in optimiz-
tively low flow rates, into the feed frame. In the hopper itself, ing die filling.
moderate stress is imposed by the weight of the stored pow- Compression. During the final compression step, the pow-
der. The resulting consolidation may inhibit flow, either be- der plug is subject to high stress. Here, the compressibility of
cause of interactions between the vessel and powder or as the the powder is relevant because it quantifies how the move-
result of powder-powder interactions. Shear strength and ment of the punches will impact the powder. In addition,
wall friction are therefore highly relevant powder properties. adhesivity indicates how likely it is that material will stick
Feed frame flow. The hopper discharge is routed to the feed to the tablet press tooling.
frame via enclosed pipe work that provides containment.
The ease with which the blend flows under gravity is impor- Choosing the best powder characterization techniques
tant here, but so too is the permeability of the powder (2). A Successful processing requires a powder that is compatible
blend with low permeability that resists the backflow of air with all stages of the process. Because it is important to un-
necessary for smooth flow will tend to pulse or ‘slug’ into the derstand how the powder will behave under many different
feed frame (see Figure 1). This can result in erratic pressure conditions, applying a single powder testing technique may
Powder Technology
Shear testing, for example, was devel-
Figure 2: Shear data classifies these two excipients as closely similar while flow
oped, and remains widely used, for the
energy measurements show that in certain circumstances they can behave quite
design and troubleshooting of hop-
differently.
pers. This test provides valuable shear
(a) strength data that is relevant to design
and operation of the feed hopper and
vanillin to the compression stage, in which ap-
ethylvanillin plied stresses are even higher. However,
5
shear testing may not be the best tech-
nique for generating data to support
4 other parts of the tablet manufactur-
Shear Stress, kPa
ing process, in which applied stresses

3
are far lower.
For example, the shear data pre-
sented in Figure 2a for vanillin and
2 ethylvanillin classifies them as closely
similar. However, as shown in Figure
2b, the dynamic flow energy measure-
1
ments tell a different story, suggesting
that the materials can behave differ-
0 ently in certain circumstances. Flow
0 1 2 3 4 5 6 7 8 9
Applied Normal Stress, kPa
energies are generated by measuring
the axial and rotational forces acting
on a paddle as it rotates through a pow-
(b) der sample (3). Downward rotation of
the paddle imposes a forcing, bulldoz-
1800
ing action while an upward traverse
measures a flow energy more closely
1600
associated with gravity induced flow.
1400
The data suggests that while these two
materials may behave similarly in the
1200 hopper, and in terms of how they co-
Total Energy, mJ
here in the finished tablet, they will be-

1000 have very differently in the feed frame.
The ease with which the materials flow
800
into the feed frame, and subsequently
into the die, as well as their response to
600
a range of blade designs, are all likely
400
to be different.
vanillin Similarly, tapped density measure-
200 ethylvanillin ments can differ from f low energy
measurements. Although tapped den-
0 sity measurements do detect changes
0 2 4 6 8 10
-100 -100 -100 -100 -100 -100 -100 -100 -70 -40 -10 that indicate differences in powder
Test Number Tip Speed, mm/s properties, they are far less sensitive
than dynamic techniques in specifi-
cally measuring flow properties (see
Figure 3). Variability in a material,
not give adequate information. Historically, the pharma- which could go on to impact flow behaviour in the tablet
ceutical industry has relied on parameters such as Hausner press, might be undetected by tapped density measurements.
Ratio and Carr’s Index, which are both derived from tapped Looking across the tablet-making process in its entirety
density techniques. More recently, the industry has begun highlights the properties that could be measured to optimize
to use shear testing. performance at each step. These include:
These approaches do have some relevance when trying • Shear properties—for the design, operation, and trouble-
to access information to support optimization of the press. shooting of hoppers
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Powder Technology
Figure 3: For this system, tapped density data are less Although tapped density
sensitive than flow energy measurements in detecting
changes in powder flowability. measurements detect changes
that indicate differences in
powder properties, they are
Flow Energy
far less sensitive than dynamic
Flow Energy
techniques.
Density
change > 1000%
Conclusion
Within the pharmaceutical industry there is increasing
emphasis on processing efficiency and more effectively
controlled manufacture. In production, it is impossible
Density change ~ 40% (max) to eliminate all the possible sources of variability, but it is
feasible to compensate for them and control their impact.
Increased Tapping
This relies on identifying, measuring, and controlling those
parameters that define processing efficiency and the quality
of the finished product.
• Bulk properties such as permeability and compressibil- In solid-dosage manufacture, achieving this goal re-
ity—to assess the response of the powder to air, the ease quires a relevant and sensitive powder testing toolkit
with which displaced air will be dispersed, and how the capable of reliably generating parameters that can be di-
blend will be impacted by compression rectly correlated with process performance. Key to this
• Dynamic properties that directly quantify flowability is the ability of a technique to effectively simulate the
under different conditions—for optimizing flow through specific processing environment, which, as an analysis
the feed frame, assessing the impact of different paddle of tableting reveals, can vary considerably. Instruments
designs, investigating the effect of air on powder flow- that combine established techniques, such as shear and
ability, and quantifying de-aeration behaviour. bulk property testing, with newer methodologies, such
Dynamic testing can also be used to assess powder stabil- as dynamic testing, can be valuable. The user can then
ity and is therefore a useful tool for investigating the likeli- tailor testing to the specific application, and access the
hood of attrition, segregation, and/or agglomeration. most complete information for process design, optimiza-
Together these measurements form a database of prop- tion, and control.
erties that can be used to tightly define an optimal blend
specification. Furthermore, such data would support in- References
vestigation into which parameters in upstream processes 1. M. Glodek et al., “Process Robustness: PQRI White Paper,” online,
ultimately dictate performance in the press and the quality www.pqri.org, Oct., 2005.
of the final product. Such strategies are highly beneficial in 2. G. Carlson and B. Hancock, AAPS Annual Meeting and Exposi-
pushing towards more efficient manufacture on the basis tion (Atlanta, GA, 2008).
of secure knowledge. 3. R. Freeman, Powder Technol. 174 (1–2) 25-33 (2007). PT

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continuous Processing
Advancing Unit Operations

For Continuous Processing
In Solid-Dosage Manufacturing
Patricia Van Arnum
T
FotograFiaBasica/Vetta/getty images
he 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 granulation
Although pharmaceutical production is a batch-processing op-
Continuous manufacturing is gradually advancing eration, specific unit operations in solid-dosage manufacturing,
through select projects of pharmaceutical such as milling or tablet compression, may be run in semicon-
companies and researchers in academia. tinuous and continuous processing steps (1). The feasibility of
developing continuous processes for specific unit operations
Granulation is one processing step moving to
requires advances in pharmaceutical equipment design and
a continuous mode. The article examines some operation. For example, to make continuous mixing, granula-
recent developments for this process step and for tion, and drying possible for small-scale operations, such as in
continuous manufacturing overall. 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
high-dose formulations and highlighted how tablets made by high-shear granulation and extrusion granulation. The research-
means of extrusion showed improved strength and low friability ers reported that a polymethacrylate binder enhanced tablet ten-
compared to traditional wet granulation, according to an Oct. sile strength with rapid disintegration in simulated gastric fluid,
13, 2011, company press release. and polyvinylpyrrolidone and hydroxypropyl cellulose binders
Researchers at Ghent University in Belgium and Com- produced less desirable tablets. Using the polymethacrylate
plutense University in Madrid recently evaluated the strengths binder, the extrusion granulation process was evaluated with
and weaknesses of several complementary process analyti- respect to the effects of granulating liquid, injection rate, and
cal technology (PAT) tools implemented in a continuous wet- screw speed on granule properties. Response variables consid-
granulation process, which was part of a fully continuous from ered in the study included extruder power consumption (screw
powder-to-tablet production line (3). The use of Raman and near loading), granule bulk/tapped density, particle-size distribution,
infrared spectroscopy and a particle-size distribution analyzer tablet hardness, friability, disintegration time, and dissolution (4).
was evaluated for the real-time monitoring of critical param-
eters during the continuous wet agglomeration of an anhydrous Academic–industrial partnerships
theophylline−lactose blend. The solid-state characteristics and par- Continuous manufacturing also is being advanced by indus-
ticle size of the granules were analyzed in real-time and the critical trial, public, and academic partnerships. For example, in Oc-
process parameters influencing these granule characteristics were tober 2011, FDA awarded a $35-million, five-year grant to the
identified. The temperature of the granulator barrel, the amount National Institute for Pharmaceutical Technology and Educa-
of granulation liquid added and, to a lesser extent, the powder feed tion (NIPTE), a nonprofit research center focused on pharma-
rate were the parameters influencing the solid state of the API. The ceutical product development and manufacturing, to improve
researchers reported that a higher barrel temperature and a higher drug manufacturing standards. NIPTE’s goal is to increase
powder feed rate resulted in larger granules (3). science and engineering-based understanding, so technologies
Researchers at Pfizer and the University of Cincinnati recently can be developed and science-based regulations can be imple-
reported on work regarding optimization for a continuous ex- mented. The FDA grant will in part by used to promote continu-
trusion wet-granulation process (4). Three granulating binders ous manufacturing as well as other issues, such as improving
in high drug-load acetaminophen blends were evaluated using small-batch production, reducing the environmental impact of
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Continuous Processing
manufacturing pharmaceutical products, and rectifying other • Achieving precise control over manufacturing of solid
drug-development and manufacturing problems. particles using continuous-manufacturing technologies
NIPTE is partnered with 10 US universities involved in the • Understanding the control of nucleation and growth
pharmaceutical sciences and engineering. The member univer- of particles by means of cr ystallization under
sities are Duquesne University, the Illinois Institute of Technol- continuous flow
ogy, Purdue University, Rutgers University, the University of • Developing continuous crystallization platforms, pro-
Puerto Rico, the University of Connecticut, the University of cess analysis tools, and strategies to manufacture par-
Iowa, the University of Kentucky, the University of Maryland– ticles for different applications
Baltimore, and the University of Minnesota. • Delivering the tools to control crystal structure, particle
In April 2011, the United Kingdom’s Engineering and Physi- shape, and particle-size distribution
cal Sciences Research Council (EPSRC) established the EPSRC • Facilitating continuous manufacture of medicines and
Center for Innovative Manufacturing in Continuous Manufac- nanomaterials with kinetic, cocrystallization, and im-
turing and Crystallization. EPSRC is the main UK government purity control (5).
agency for funding research and training in engineering and In 2007, Novartis formed a $65-million, 10-year research
the physical sciences. The University of Strathclyde is leading collaboration with the Massachusetts Institute of Technology
the EPSRC Center for Innovative Manufacturing in Continu- (MIT) to launch and fund the Novartis–MIT Center for Con-
ous Manufacturing and Crystallization, which also involves tinuous Manufacturing to develop new technologies to replace
the Universities of Bath, Cambridge, Edinburgh, Glasgow, the pharmaceutical industry’s conventional batch-based system
Heriot-Watt, and Loughborough. Industry partners include with continuous manufacturing processes.
GlaxoSmithKline, Pfizer, AstraZeneca, Fujifilm, Croda, The Engineering Research Center For Structure Organic
Genzyme (now part of Sanofi), NiTech Solutions, Phoenix Particulate Systems, a multi-university consortium consist-
Chemicals, Solid Form Solutions, and British Salt. ing of Rutgers University, Purdue University, the New Jersey
The EPSRC Center for Innovative Manufacturing in Contin- Institute of Technology, and the University of Puerto Rico
uous Manufacturing and Crystallization has identified several at Mayagüez, is another academic-partnership involved in
key research challenges: 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

Tableting
Multilayer Tablets: Key

Challenges and Trends
An Industry Rountable
S
olid dosage forms are the most popular method of
drug delivery and although tablets are widely estab-
N. EvElEigh/photodisc/gEtty
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
Experts in solid dosage discuss the formulation solid dosage for a special roundtable on the formulation
and manufacture of multilayer tablets. Fixed- and manufacture of multilayer tablets. We also spoke to re-
dose combinations, which have raised much searchers about fixed-dose combinations, an area that has
raised controversy, regarding adverse effects. Participants
controversy in the industry as experts mull the
in the roundtable include: Marcus Behrens, sales director
potential for adverse effects, are also discussed. 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 demand
PharmTech: 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)
Tableting
From left to right: Marcus Behrens (IMA Kilian), James Calvin (Elizabeth
Figure 1: Demand for reformulation (PharmTech poll).
Companies), Doug Kirsch (Natoli); LakshmiDevi Ethirajan (Tedor Pharma) is
not shown.
What is driving manufacturers to reformulate or reinvent
currently marketed solid dose pharmaceutical products?
40% 49%
11%
 Need to renew patents

 Availability of new excipients
 Opportunity to improve efficacy and patient compliance
hot topics in the pharma industry. These novel delivery produce. For instance, for core tablets, developments now
systems have been essential not only in formulating new enable the core to be positioned more precisely within
products, but also in helping pharmaceutical companies the tablet.
to extend patents. Kirsch (Natoli): Multilayer tablets have been manufac-
Ethirajan (Tedor Pharma): Among other advantages, tured for a long time; more than 50 years that I know of.
triple-combination therapy in a single-dosage form is being They are not going away.
used to promote better treatment adherence by providing A new possible need for layered tablets is the recent
a convenient single tablet. As well as increasing patient FDA draft guidance for industry on tablet scoring. Uni-
compliance, multilayer tablets can help to reduce the cost form dosage and assurance that a patient is capable of
of medication. splitting the tablet properly are two of its concerns. Accu-
Break Pharmaceuticals developed and patented a unique
Future success method using layered tablets to address these issues. The
PharmTech: Considering the split drivers of compliance first (bottom) layer is a drug-free placebo. The second
and patent extension, do you think multilayer tablets will (top) layer containing the API(s) is scored deep enough to
continue to be successful in the future? reach the second layer. The first inactive layer is merely a
Behrens (IMA Kilian): If we think of fixed-dose holder for the active second layer and when broken, result
combination drugs as a way to treat two closely related in a uniform dose. A trilayer tablet with an inactive center
diseases, or to improve compliance and thus efficacy layer for split dose combinations has also been developed.
of prescribed medicines, we believe that this trend will Simple, yet brilliant.
continue. However, multilayer tablets could be a less fre- Ethirajan (Tedor Pharma): Multilayer technology will
quent option if, in the future, the drugs are designed to continue to be an option in the future for several reasons:
be mixed into a unique powder that can be processed in • Pharmaceutical companies will file new patents or ex-
a standard tablet press. tend existing patents on their company name on com-
Today, most combined actives are existing drugs. In the bination product to win market exclusivities.
future, a higher number of combinations will be achieved • Generic-drug makers may use new technology as an
with new formulations that are specifically designed to be option to work around existing patents for markets
combined from the development stage. In this case, the product.
properties of the different compounds can be optimized to • Advancements in the technology by equipment manu-
be combined, minimizing possible interactions. facturers who recognized the importance of meeting
Calvin (Elizabeth Companies): I believe that the de- regulatory requirements to market their high speed
mand for multilayer and tablet-in-tablet technology will machines for production.
continue for many years to come, particularly as new Most importantly, a single tablet containing multiple
high-potency drugs, which are often combined with other medications can be both cheaper and more convenient than
drugs in a single multilayer tablet generate a demand for separate tablets.
layer technology. Many matrices are incompatible with
one another, but with multilayer tablets, formulators can Formulation
insert an inert barrier layer between the incompatible PharmTech: When formulating multilayer tablets, what spe-
matrices to prevent an interaction. Also, developments cial considerations are required for factors such as levels of
in the technology have made multilayer tablets easier to fines, bulk densities, and granulation properties?
Behrens (IMA Kilian): For efficient tableting, granule sity granulation, it would normally be used on the first layer
f low is crucial and a certain amount of fines is needed if the tableting press has a limitation of the upper punch
to guarantee proper filling and binding of the tablet. It penetration of the layer tamping stations that regulate the
is also important that the tableting machine is designed depth of fill of the consecutive layers.
so that the filling range can cope with bulk density. In Kirsch (Natoli): The level of fines must always be con-
addition, the system should avoid the carry-over of par- sidered, even for non-layered tablets. Excessive fines will
ticles or fines. 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
“The multilayer tablet is proper tablet compressibility, it is critical that these are
kept to a minimum when compressing layered tablets oth-
a viable way to combine erwise cross contamination from one layer to the next will
different actives for a synergic be increased as fines will pass under feeders and scraper
blades. Bulk densities are also a consideration because
therapeutic effect...,” — Marcus light or airy granulations require increased depth of fill
and precompression. Pre-compression of the first layer is
Behrens, IMA Kilian required for clear demarcation lines between the layers.
If the press does not have sufficient upper punch penetra-
Calvin (Elizabeth Companies): When utilizing a tablet tion to pre-compress/tamp the first layer, then the desired
press with the proper powder-feed system, there is usually weight may not be achieved and there will be insufficient
no need for any special considerations or factors such as volume in the die bore for the next layer. Some modern
levels of fines or granulation properties to be determined. presses are only capable of 4 mm upper punch penetra-
The only consideration would be the bulk density of the tion, whereas many older presses were capable of almost
granulation. Depending upon which layer is the lighter den- Continued on Page s28
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Tableting
Fixed-Dose Combinations
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.
PharmTech: Why have FDCs been criticized in the past? However, manufacturers have taken note of this and addressed the
Gupta (Imperial College London): The use of FDCs was problem in certain cases, but the criticism is justified because the very
previously discouraged because of cost considerations, lack of existence of the FDC discourages adjustment of doses to the patient’s
flexibility in dose titration, and doubts over the bioavailability of needs, and may also lead to overdosing or underdosing of one or more
the individual components (compared with the bioavailability of the of the active ingredients present. Moreover, busy prescribers may not
constituent components, when given separately). Another concern notice the dose of each active ingredient present in an FDC and it could
was that the use of FDCs would be associated with the increased risk encourage polypharmacy.
of adverse events. Over the last few years, however, the findings of
several clinical trials and observational studies have refuted most of PharmTech: Despite criticism, some data have suggested that
these concerns (1–4). compliance is increased. Could you explain why you agree or disagree
Findings from recently conducted clinical trials have virtually removed with this statement?
any doubts over the comparative efficacy and safety of an FDC versus its Gupta (Imperial College London): I agree that there is a
corresponding free-drug combination. Moreover, in several situations, significant body of evidence confirming directly or indirectly that
the use of FDC was associated with significantly improved efficacy. For the use of an FDC is associated with improvement in compliance.
example, in the ACCOMPLISH Trial, blood pressure control rates (within Several observational studies have shown an inverse relationship
first six months) improved significantly among previously treated between the number of prescribed medications and concordance
hypertensive patients, from 37% to 73%, with the use of a single pill with them. A few qualitative surveys on patient perception have
FDC of two antihypertensive agents. Another trial using a low-dose FDC, largely produced supportive data, suggesting that the use of an FDC
STITCH Trial (Simplified Treatment Intervention to Control Hypertension), would be more convenient for patients, and encourage compliance
found that those allocated to treatment with an FDC compared with the and adherence with medications. The findings of our meta-analysis,
usual care were more likely to have a better blood pressure control, with using evidence from cohort studies and clinical trials, have confirmed
no adverse effect on tolerability. previous indirect findings: our analyses found that, compared with a
Other studies have also shown that the total costs (direct and indirect) free-drug combination, the use of an FDC was associated with a 21%
related to the use of any FDC is likely to be lower than the use of its significant increase in compliance and a 54% increase in persistence
corresponding free-drug combination, particularly because of a reduction with therapy.
of indirect costs related to disease complications. Indeed, a quick look Udupa/Sreedhar (Manipal University): There are several
at the costs of available FDCs in the UK shows that the direct cost of advantages offered by FDCs. Many studies have shown that FDCs increase
several FDCs is similar or cheaper than the cost of the two constituent both patient compliance and adherence. FDCs also simplify treatment
components given separately. Additionally, the cost to patients at the regimens. Physicians feel that it is convenient to prescribe FDCs rather
point of delivery is cheaper with an FDC compared with the prescription than single component products, and this sentiment is often shared by
of two components separately when patients have to pay for prescription. patients. It is also generally believed that FDCs are cheaper and reduce
A recent study has also shown that costs incurred by the patient (either as the costs of logistics, which is especially important when FDCs need to be
co-payment or otherwise) has an inverse relationship with adherence and distributed to remote places.
concordance with medication. Lastly, the improved and easy availability
of several different dose compositions of an FDC have made it easier for PharmTech: Can you give examples of successful, rational FDCs?
physicians to up-titrate medications with little difficulty. Gupta (Imperial College London): Currently there
In summary, I believe, it is no longer justified to persist with an attitude are numerous examples of success stories with FDCs. An FDC of
of disdain against the use of FDCs. antituberculosis medications, compared with the corresponding
Udupa/Sreedhar (Manipal University): The single most free-drug combinations, was associated with significantly higher
important factor that FDCs have been criticised for is dose titration. treatment rates and significantly lower adverse effects. Similarly,
Dose titration of one or all the active ingredients present in an FDC is among those with HIV, the use of an FDC of anti-HIV drugs has
not possible, which is crucial when both actives require dose titration. shown greater rates of remission. In comparison to these examples,

the success stories with the use of FDC in the field of cardiovascular PharmTech: How do you think the benefits and disadvantages
medicine are not that dramatic. However, there is a rapidly growing of FDCs shape up against one another? Should the industry pay more
body of data, suggesting that the usefulness of FDCs in cardiovascular attention to potential FDCs or would the time be better spent on other
and metabolic medicine is likely to be no different than that seen in areas of innovation?
other fields of medicine. Gupta (Imperial College London): This is an interesting
In cardiovascular medicine, the main utility of FDCs is mediated question, but there is no readily available answer. In my opinion,
through improved compliance, which in turn may increase the each new FDC formulation should be based on a thorough
treatment efficacy and decrease the outcomes. This hypothesis is understanding of disease mechanism, as well as the mechanism of
partially supported by findings of our meta-analyses: the use of FDCs action, pharmacokinetics and pharmacodynamics of each constituent
(compared with the use of corresponding free-drug combination) was component—separately and in combination.
There are a few FDCs that are more
“Many studies have shown that FDCs frequently prescribed over the other because
of the prevalence of the clinical situations that
increase both patient compliance and they are most effective in. However, given
the numerous clinical prescribing situations,
adherence,” — Dr. N. Udupa and Dr. Sreedhar, I believe all FDCs will have their own niche in
treatment settings. Having said that, I believe
Manipal University that there are only a finite number of possible
FDCs and with the rapid introduction of new
associated with a greater (albeit statistically insignificant) reduction. FDCs, the market will probably be saturated in the next few years or
Elsewhere, a few observational studies have shown that the improved so. For long-term sustainability, the pharma industry should spend a
adherence with medications is likely to be associated with greater significant amount of time on other areas of innovation, including the
cardiovascular benefits. development of new drugs and effective drug delivery mechanisms.
Another potential advantage with the use of FDC is a possible Udupa/Sreedhar (Manipal University): Benefits and
reduction in adverse effects. In our meta-analysis, compared with the disadvantages should be looked at simultaneously and not individually
corresponding free-drug combination given separately, allocation to FDC when evaluating an FDC. If there is considerable evidence that the
was associated with lower adverse event rates. The use of a low-dose proposed FDC has more benefits than disadvantages, then it’s a definite
FDC of two drugs as an initial therapy (in several situations) may have ‘go’ situation.
significantly lower adverse events and a better tolerability, than either of The pharma industry should definitely explore the potential benefits
the medication alone. A classic example of this is an FDC combination of FDCs offer over their individual component products. It is difficult for
an angiotensin-converting enzyme (ACE) inhibitor and a calcium-channel small- to medium-scale companies to bear R&D costs and even larger
blocker (CCB) is likely to be associated with lower incidence of ankle companies are finding it risky to develop new drugs and so most pharma
swelling, compared with the same dose of CCB alone. companies are now in search of new business models. One of these
Udupa/Sreedhar (Manipal University): Fixed-dose options is to develop FDCs of existing individual components that are co-
combinations are especially useful when treating diseases like human prescribed in order to help preserve patents.
immunodeficiency virus/acquired immunodeficiency syndrome (HIV/ When developing FDCs, however, companies must consider the safety
AIDS), malaria, and tuberculosis where more than one drug is usually and efficacy of the active components in combination, the benefits
recommended. There are also certain other conditions and diseases, of simultaneous use of active ingredients and possible interaction
such as cancer, cardiovascular diseases, diabetes, neuropsychiatry between the components. Fixed-ratio combination products are usually
and pain where FDCs may offer benefits. Some successful and rational considered for marketing approval by regulatory authorities only when
FDCs include: the dosage of each ingredient meets the requirements of a defined
• Antiretroviral combinations: abacavir + lamivudine, tenofovir population group and when the combination has a proven advantage
disoproxil fumarate + emtricitabine and efavirenz + tenofovir + over single compounds administered separately in its therapeutic
emtricitabine. effects, safety, or compliance.
• Antimalarial combinations: artesunate + amodiaquine, artemether +
lumefantrine and amodiaquine + sulphadoxine + pyrimethamine. References
• Antitubercular combinations: Rifampicin + Isoniazid + Pyrazinamide. 1. A.K. Gupta, S. Arshad and N.R. Poulter, Hypertension, 55(2), 399–407
• Hypertensive combinations that provide better blood pressure (2010).
control: Amlodepine + Atenolol, Amlodepine + Losatan and 2. K. Jamerson et al., N Engl J Med., 359, 2417–2428 (2008).
Irbesartan + Hydrochlorthiazide. 3. ADVANCE, “ADVANCE Trial — Blood pressure lowering arm results”.
• Antidiabetic combinations that provide better glycaemic control: www.advance-trial.com
Glibenclamide + Metformin, Glipizide + Metformin and Pioglitazone 4. R.D. Feldman et al., presentation at Scientific Sessions 2007 of the
+ Metformin. American Heart Association (Orlando, 2007). PT

Tableting
Continued from Page s25 present in the multilayered machines are non-metallic
10 mm penetration, which, in many cases, made them in nature; hence, it is imperative that the use of abrasive
better suited for layered tablets. Granulation properties excipients that may ruin these scrapers is avoided. Using
would be much the same as with non-layered tablets with excessive amounts of lubricants should also be avoided
the exception of reduced fines; good flow and compress- because these may interfere with adhesion between lay-
ibility are always desired. ers. Excipient choices should also be based on the func-
Ethirajan (Tedor Pharma): It is beneficial if both layers tionality of a particular layer (immediate release versus
have relatively equal physical properties, such as the amount controlled release).
of fines, bulk density and granulation properties. It is also PharmTech: How can layer cross contamination be avoided?
ideal to maintain granule size less than one half of the layer Behrens (IMA Kilian): Product losses can be very high
thickness to achieve a clear scrape-off. Specifically, fines when making layered tablets. Usually strong vacuum as-
below 200 meshes can smear or coat the turntable surface piration is used to clean the residual product on the die
and it may not be possible to achieve a clean scrape-off, table after the dosage of each layer, thus preventing cross
which can lead to layer cross-contamination. 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.
“It would be advisable to Calvin (Elizabeth Companies): Layer cross-contamina-
invest in a purpose built tion can be avoided in a few different ways. For example,
ensuring the feed frame is correctly adjusted and not leak-
press engineered for layered ing powder, properly adjusting the vacuum being applied to
the front of the feedframe to keep the die table clean, and
tablets,” —Doug Kirsch, Natoli. 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’
Cross-contamination (a delrin cover that is held in place against the die table with
PharmTech: How can common formulation issues, such as spring steel to keep any granulation form slinging out of the
the combination of incompatible products, be overcome? die through centrifugal force) may be needed if any powder
Calvin (Elizabeth Companies): The incompatibility of loss is incurred due to centrifugal force.
multiple drug matrixes is often paramount in the decision of Kirsch (Natoli): Proper press set up is essential. Turret
a new product design process. As mentioned, however, this die tables have a certain amount of vertical run out. Often
issue can be overcome by keeping the matrices separated by overlooked is the simple task of indicating a die table to
an inert ‘barrier’ layer to prevent drug interaction. locate the high point. Feeder clearance must be set at this
Kirsch (Natoli): Incompatible APIs are the main driver point to achieve a minimal amount of clearance between
for layered tablets. They enable incompatible ingredients to the feeder and die table to reduce granulation loss. Scraper
be administered in the same tablet without degrading the blades must be in good condition and free floating on the
actives. As for excipient choice, this is why we have R&D; die table to reduce cross contamination. Die tables must
use what works. also be in excellent condition as any wear or damage will
Ethirajan (Tedor Pharma): Incompatibility between contribute to granulation crossover. Proper dust extrac-
the tablet components can be overcome by having the in- tion is also needed as presses suited for layered tablets
compatible ingredients in different layers. It is critical to generally have more and/or specifically designed vacuum
understand the physicochemical properties of the drug sub- nozzles. Again, reduced fines would be important. An-
stance, and preformulation compatibility studies will help other crucial point is that skilled press set-up technicians
identify such incompatibilities so that certain excipients and operators are a must.
can be avoided or be separated into different layers for bet- Ethirajan (Tedor Pharma): Scraper and seal conditions
ter drug product stability. Multilayered technology is used of the feed frames are very important. It is also essential
in many instances to overcome incompatibilities between that excess granulation passing the scrape-off be vacuum
drug substances that need to be administered in a single cleaned so that fines from one layer don’t cross contami-
dosage. Occasionally, in the case of three-layer tablets, a nate the other. Reduced fill cams may be used to reduce the
thin placebo layer may be used between the outer active amount of granulation that needs to be scraped off from
layers to avoid incompatibilities. overfill of the die.
Another vital part in developing multilayered tablets is
excipient selection. It is preferable to use excipients that Control
are compatible with the drug substances in both the layers PharmTech: How can the weight of individual layers be
to maximize drug product stability. Generally, scrapers monitored and controlled accurately?
Behrens (IMA Kilian): When producing bilayer tab- compared to the strain gauge that would be required for
lets, the in-line control of production, combining com- final tablet compression.
pression force measurement and statistical weight check The secondary method is to select a multilayer tablet
are challenging for several reasons. If the compaction press that automatically collects sample tablets from each
force for layer one is extremely low, it could be very dif- layer at regular intervals and then sends them to a weight
ficult to obtain a clear signal from the strain gauges. Low testing unit, which would be included in the press control
force compression rollers are available to help deal with feedback loop, to provide in-process checks along with
this. The reduced mass ensures more accurate and reliable weight control.
measurements. Another critical point is statistical sam- Kirsch (Natoli): Tablet press manufacturers will be
pling of the layers for weight checking. For sampling, the responsible for this through improved technology and
first layer has to be compressed at a higher force to achieve 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
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
Tableting
the formulation is understood and the design space can In-process controls and PAT
be exploited to deliver a controllable process. Controlled PharmTech: The pharma industry is paying increased atten-
processes deliver a product with the required critical tion to in-process controls and process analytical technology
quality attributes that define what is to be delivered to (PAT). What are the challenges of applying these methodol-
the patient. ogies to multilayer tablets over standard single layer tablets?
Behrens (IMA Kilian): PAT systems based on transmis-
Aesthetics sion or reflection are seldom used on monolayer tablets. The
PharmTech: Aesthetically, what consideration should be amount of validation is high, and even more complex for
given to color? bilayer or multilayers. It is also difficult to repeat the mea-
Kirsch (Natoli): Aesthetics are always important to the suring results on each layer. The industry has to put more
consumer. However, as a manufacturer, the first concern efforts into this issue.
would be, what the cost is and how well does it compress? Calvin (Elizabeth Companies): The only additional chal-
Colors as well as flavors can affect tablet compression. Some lenge when pressing a multilayer tablet versus a standard
may be more heat sensitive than others, resulting in picking tablet relates to process control to ensure that the prior layer
or sticking issues. Others may have excessive fines resulting in is at the correct weight before allowing any automatic weight
punch and die binding, which increases tool and press wear. change to occur. The first layer must be in the correct weight
range before any changes happen to the second layer. In the
“Excipient choices should case of a three-layer tablet, the first and second layers must
be in the correct weight range before allowing the third layer
also be based on the func- to make any weight adjustment.
Kirsch (Natoli): PAT is best used during development to
tionality of a particular layer,” understand the variables involved in achieving the formula-
tion design for a quality tablet. Transferring the PAT meth-
— LakshmiDevi Ethirajan, ods to manufacturing is necessary only when the informa-
Tedor Pharma tion generated by the measurements is required to achieve
the necessary process control to deliver the desired product.
A common error is developing a new product in R&D However, PAT measurements can provide information for
on a slow, partially tooled press and then submitting a New feedback control, which can offer the manufacturer an op-
Drug Application before testing it on a production machine. portunity to move toward real-time release of a product. If
The R&D press may not even have the same type tooling. traditional tablet press variables are properly controlled and
If the product was developed on a ‘D’ tooling press and the a quality granulation is delivered to the tablet press, then the
production press was a ‘B’, dwell time would be reduced, due diligence time spent in process development pays off
resulting in poor layer cohesion or soft tablets. Partial sets of with a robust manufacturing process that does not require
tooling will result in more time under pressure, therefore in- process analytical instrumentation.
creasing tablet hardness. Again, poor layer cohesion and soft Ethirajan (Tedor Pharma): All controls that apply to a
tablets could be an issue on a high-speed press. Production single layer tablet must be performed for each different layer
presses run at higher speeds and temperatures, increasing in a multilayer tablet. For example, in a bilayer tablet, the
possible sticking, picking, laminating, and capping issues. granulations for each of the layers are manufactured sepa-
The criteria for color or flavor choice should be what is rately. Both layers have a drug, and then both layers must be
least costly and runs best on a production press and not just monitored and controlled for drug uniformity in the blend/
what ‘looks pretty.’ There is a middle ground somewhere for granulation. During compression, in-process controls for
marketing and production. Marketing will not have to deal weight must be used for both layers. Hardness for the first
with the production headaches. It may cost thousands or layer and hardness for the final tablet must also be moni-
hundreds of thousands to do a trial on a production press, tored. If controlling the specification for one of the layers is
but would be more cost effective than wasting millions more challenging, it also affects the formulation and scale-
fighting it in full-scale production. up of the entire process.
Ethirajan (Tedor Pharma): Colors play an important
role in multilayered tablets. Firstly, it is a method of visual PharmTech: Batch yields for multilayer tablets can often
process control during compression. The extent of cross be lower. What future improvements would help increase
contamination, if any, can be easily seen when granulations yields?
of different colors are mixed during compression. When a Behrens (IMA Kilian): Vendors have developed many
color coating is not present, colored tablets also give a visual new systems and machines that can help in this area. I
description to the drug product. In the case of over-the- believe that one important feature of such systems is user-
counter products, color and aesthetics play a major role in friendly software. In addition, simple features that enable
consumer choice. shorter set-up times can be beneficial.
Calvin (Elizabeth Companies): I disagree; the batch speeds. Presses are available with 100 or more stations of
yield is not affected by the reduced tableting speed, but it is tooling which will certainly increase output. It would be
reduced by several other factors. Operating a layer press is advisable to invest in a purpose built press engineered for
the same as operating several presses at the same time; for layered tablets. Retro-fitted or converted presses do not
example, in the case of a three-layer press, you have three function as efficiently.
different powder feeders possibly containing three differ- Ethirajan (Tedor Pharma): Production rate yields are
ent granulations that can contribute to reduced yield. The generally lower. This is because a two- or three-sided ma-
feeders can contribute to the loss if care is not taken during chine only makes a single tablet with each head revolution.
set up, or if they are not properly adjusted to the die table Also, the need for vacuuming off the granulation that passes
and are allowed to leak powder. The second major contrib- the scrape off after each fill station causes higher granula-
uting factor to batch yield is the vacuum. If the vacuum tion loss relating to low batch yield. PT
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
What’s in your capsule?
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 Active 1 (µg) Active 2 (mg)
to properly adjust the powder feeders
to the die table, correctly balancing
the vacuum and by collecting the Excipients
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, The FOSS XDS MasterLab™ is a
tablet hardness, cross contamina- Near-Infrared (NIR) Analyzer that
tion, or other compression issues provides you with rapid, accurate
may result in a further slowing of and non-destructive chemical analysis
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the press. Press manufacturers are in the laboratory and during the multiple tablets or vials.
always researching ways to improve manufacturing process.
multilayer press efficiency. Layer FOSS is the world leading supplier of NIR
sampling typically slows produc- The XDS MasterLab offers pharmaceutical products and services with over 18,000
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tion. Fette has introduced several method covering the full array of years of NIR experience ensures that we
methods to reduce sampling de- solid dosage forms: layered, coated or will be there when you need us.
lays and a ‘punches up’ option to cored tablets, capsules, caplets, geltabs
eliminate second layer only tablets. and gelcaps. The versatile sampling Please contact us for more information.
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Older layer presses discarded excess
automated and unattended reflectance
product whereas product recircula-
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individual layers allowing for higher
magenta
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black ES26249_PTsupp0312_031.pgs 02.29.2012 07:34 ADVANSTAR_PDF/X-1a
Tableting
Key Formulation Factors

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.
PharmTech: How have advances in performance and clinical outcome over its shelf life. There are no specific
pharmaceutical manufacturing technology regulations for multilayer tablets or any other pharmaceutical dosage
influenced the development of multilayer form, but 21 CFR 314 and 21 CFR 320 address the various issues that should
tablets? be addressed in the submission.
Sayeed (FDA): Improvement in the
understanding of the material science PharmTech: How can manufacturers best use a quality-by-design
(physical, chemical, and mechanical) and approach to support the development of a new multilayer tablet?
the engineering of the tableting machine Sayeed (FDA): Quality by design can be used to
FDA’s Vilayat A. Sayeed

to control weight of individual layer/s, total comprehensively put forth the understanding of the product
tablet weight, and compression factors formulation (drug substance inherent properties, excipient
for the layers are responsible for the advancement in pharmaceutical properties, and variability) and manufacturing process on product
technology of the multilayer tablets. performance. The design elements should be based on prior
knowledge, risk assessment,
“The established controls and specifications and process controls in
achieving the multilayer tablet
should be based on the sound scientific of desired quality. To further
enhance the understanding
principles, ICH and regulatory agency where applicable, the
manufacturer should conduct
guidance, and should be fully justified,” design of experiment studies to
develop and identify critical to
— Vilayat A. Sayeed, FDA quality attributes and process
parameters. This systematic
PharmTech: What critical factors do manufacturers need to be aware approach of building quality by having a mechanistic understanding
of when producing multilayer tablets? of variables and their impact on the manufacturing process and the
Sayeed (FDA): Critical factors can be broadly divided into material performance of the product with limited dependence on the end-
attributes and process parameters. Material attributes such as: product testing should be the focus and the intended use of quality
compatibility, compressibility, compactability, adhesion, tensile strength, by design.
flow properties, porosity, density, layer relaxation during shelf-life and
storage and propensity for in-vitro and in-vivo delamination are some of PharmTech: Are there any other issues specific to multilayer tablets
the factors a manufacturer must understand in producing a multilayer that companies will need to address in regulatory submissions?
tablet. The process parameters includes impact of lubricant in each Sayeed (FDA): The knowledge gained by applying the scientific
blend, tamping force for initial layer(s) compression, final compression principles and risk management tools during the pharmaceutical
force for tableting, and press speed. Both of these factors have to be fully development must be fully discussed and those functional
understood for making a quality multilayer tablet. relationships that are linked to product performance must be clearly
presented in the regulatory submission. In addition to providing a
PharmTech: Which regulations, in particular, are applicable to complete mechanistic understanding supported by data developed
determining these critical factors? through the application of scientific and quality risk management
Sayeed (FDA): Regulations are written to address and capture the tools, the applicant should also provide the relevance and justification
safety, efficacy and quality concerns, regardless of how the product is of the product design to the product performance and clinical
designed and manufactured. It is the responsibility of the sponsor to outcome. The established controls and specifications should be based
study, understand, and establish controls in the process to ensure that on the sound scientific principles, ICH and regulatory agency guidance,
the manufacture of a drug product can provide the intended product and should be fully justified. PT

Multilayer Technology
A Q&A with Accu-Break
Pharmaceutical Technology speaks with David Breach, a technical consultant for formulation development and
manufacturing at Accu-Break Pharmaceuticals.
PharmTech: Accu-Break has used multilayer through the middle drug-free layer. When appropriate, the patient
technology in an innovative way, could you could then resume taking the whole tablet, which allows some
please describe the reasoning behind the dose flexibility without having to stop the prescription entirely.
David Breach, Accu-Break drug-free layer? The tablet could also be used to initiate treatment with a single
Beach (Accu-Break): We have developed two distinct multilayer agent and then add the second and, thus, efficiently transitioning
tablet technologies, known as Accu-B and Accu-T, which incorporate a the patient into a convenient FDC without the need for separate
drug-free layer. With the Accu-B technology, the dosage form has two prescriptions during the titration phase.
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 PharmTech: Does the use of a drug-free layer to separate incompatible
and foremost, given the deep score in the drug layer, the drug-free layer APIs require further consideration specific to the choice of excipient(s)?
forms a backbone that gives the finished dosage form mechanical strength Beach (Accu-Break): Excipient choices are broad and specific
to withstand packaging and shipping operations. Secondly, the drug-free requirements are not unique to the technology, meaning common
layer is the fracture plane for the Accu-B tablet. The tablet can be broken excipients are readily adaptable for use in Accu-Break technologies. For
through the score and the fracture occurs in the drug-free layer. Compared Accu-B tablets, the requirement for a strong backbone in the drug free layer
with a conventionally scored tablet, the Accu-B bilayer design ensures necessitates the use of excipient materials with good compressibility (e.g.,
partial dosing accuracy and eliminates concerns over loss of mass. Using microcrystalline cellulose). Typical finished tablet hardnesses are more than
the Accu-B technology, scored tablets can be made that would satisfy 20 Kp. In addition, in an immediate release product, the desire to have the
the testing and data requirements for both the European Pharmacopeia’s drug free layer separate rapidly from the active containing layer typically
Monograph 0478 and the FDA’s recently proposed Guidance for Industry, requires the use of higher levels of disintegrant in the drug-free layer.
Tablet Scoring: Nomenclature, Labeling, and Data Evaluation.
Our Accu-T technology uses up to five layers in a taller-than-wide PharmTech: Why have fixed-dose combination (FDC) drugs been
tablet, and the incorporation of drug-free layers serve one of two criticised in the past?
purposes: Beach (Accu-Break): The largest historical criticism of FDCs has
• The drug-free layer provides a physical barrier between active come from the lack of dose flexibility. Taking antihypertensive FDCs
ingredients. This barrier allows the formulation of incompatible as an example, treatment is typically initiated with a single agent,
actives with no worries about co-mixing and resultant physical or which is titrated to a maximum tolerated dose. If the desired effect
chemical stability issues. The technology utilizes machinery that on lowering blood pressure is not achieved, a second agent is added,
can produce tablets with up to five compressed layers so the use of which also requires titration and can lead to lowering the dose of the
more than one drug-free layer can facilitate a “poly pill” with three first agent. A third agent is sometimes added to the mix, or substituted
different API-containing formulations. for one of the initial drugs. This process continues until the patient’s
• A drug-free breaking layer is incorporated into the middle of an blood pressure is within the target range, and then the physician looks
Accu-T tablet and can be used to separate the drug-containing for an option to transition the patient to an FDC that contains APIs at
layers. Since the drug-containing layers are physically located the effective dose for that patient. This is done of course to simplify the
at the top and bottom of this taller-than-wide tablet, breaking dosing regimen for the patient in an attempt to maintain adherence
the tablet through the middle drug-free layer separates the dose to the regimen. Problems arise when a dose adjustment is necessary
into exact halves. Unique fixed-dose combination (FDC) tablets due to the inflexibility of traditional FDCs. The convenience of a single
can be made where the top and bottom layers contain different dosage form is offset by the inability to manage dose adjustments
actives. In this configuration, the two different drug layers can be without the need for new prescriptions. If a patient is transitioned to
separated if desired by splitting the tablet through the middle- an FDC, inevitably an adjustment will be made to their dose(s), their
drug free layer. Patients taking antihypertensive FDCs can be regimen, the specific drugs being used, or all of the above. So, from
confronted with side effects that result from one of the drugs that perspective, the criticism is justified. However, for those patients
within the FDC, resulting in prescription discontinuation. With who are effectively managed using FDCs, the ability to take lower doses
the Accu-T FDC tablet design, a patient could suspend treatment of two or more medications in a single dosage form is highly desired,
with one of the drugs in the FDC by simply breaking the tablet especially if it is a once-a-day regimen. PT

Anticounterfeiting
Physical-Chemical Identifiers
A Q&A with FDA on the Final Guidance
Moderated by Angie Drakulich
FDA answers key questions about the October Background

2011 guidance on using physicalÐchemical FDA published in October 2011 the final guidance, Incor-
poration of Physical- Chemical Identifiers (PCIDs) into Solid
identifiers in solid oral dosage products to help
Oral Dosage Form Drug Products for Anticounterfeiting (1).
prevent and avoid counterfeiting. 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
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Anticounterfeiting
permissible direct food additive, a food substance that is laser scanning devices, excitation/fluorescence detection).
GRAS, or an ingredient listed in the IIG than for a novel Some identifying characteristics, such as pigments or fla-
PCID. According to the guidance, the agency would expect vors, could be easily observed by patients, healthcare prac-
to see information about items such as the PCID’s chemi- titioners, and pharmacists. Others could require the use of a
cal composition, the rationale for selecting the PCID, how detection instrument (e.g., a scanner, photometric detector,
the PCID is integrated into the product, the location of the mass spectrometry).” What is the expectation in terms of
PCID in the product, and the relevant physical–chemical who has responsibility—for example, healthcare providers
attributes of the PCID. or pharmacists—for determining and authenticating the
Pharmaceutical Technology asked the agency a few follow- presence of a PCID before patient distribution?
up questions about the guidance and plans going forward.
The responses are provided by an FDA Spokesperson. FDA: There is no intention by FDA to place a burden of re-
sponsibility on healthcare providers to authenticate drugs
PharmTech: Location and presence of a PCID in a solid dosage by determining the presence of a PCID before patient dis-
form is crucial in order to avoid interaction with the drug tribution.
substance. What are the key concerns that manufacturers
must consider in this regard (e.g., release rate, drug sub- PharmTech: Are there plans to extend the guidance beyond
stance interaction)? solid dosage forms?
FDA: There are no plans

The key concerns for the presence and at this time to extend the
location of a PCID in a solid oral dosage form guidance on PCIDs beyond
solid oral dosage forms.
are potential interactions with the drug
PharmTech: What other an-
substance and potential impact on the drug ticounterfeiting measures
does FDA recommend for
product release rate. oral solid dosage forms in
addition to PCIDs?
FDA: The key concerns for the presence and location of a
PCID in a solid oral dosage form are potential interactions FDA: FDA encourages manufacturers to continue exploring
with the drug substance and potential impact on the drug promising technologies for use as anticounterfeiting mea-
product release rate. Interactions with the drug substance sures. These may include radiofrequency identification
could cause degradation. Interactions with rate-controlling (RFID), nanotechnology, encryption and other track-and-
exipients could impact the release rate of extended release trace technologies.
or delayed release dosage forms.
PharmTech: Manufacturers can submit information about
PharmTech: It is recommended that industry use already ap- their intent to use a PCID in a solid oral dosage product
proved direct food additives (e.g., those listed in GRAS or in an NDA or ANDA or as a postappoval change. Some
IIG) at the lowest specified levels to avoid adverse reactions. industry members have raised convern over confidential-
Does the agency have plans to create a list of specific PCIDs ity. Can you confirm that PCID information submitted in
for the pharmaceutical industry to be used in the future? these documents is confidential and therefore protected
Will PCIDs that are not in the GRAS or IIG be considered from would-be counterfeiters?
by the agency if submitted by an applicant for use?
FDA: FDA confirms that information on PCIDs submitted by
FDA: The agency does not have plans to create a list of specific applicants or master file holders is considered confidential.
PCIDs for the pharmaceutical industry. Proposals for the
use of PCIDs that are not in the GRAS or IIG lists can be Reference
submitted by an applicant for evaluation by FDA. 1. FDA, Guidance for Industry: Incorporation of Physical- Chemical
Identifiers (PCIDs) into Solid Oral Dosage Form Drug Products
PharmTech: According to the guidance, “There are various for Anticounterfeiting (Rockville, MD, October 2011).
available means for presentation and detection of PCIDs 2. FDA, Counterfeit Drug Task Force Report: “Combating Coun-
(e.g., photolithography, holography, optical microscopy, terfeit Drugs” (Rockville, MD, February 2004). PT

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K E E P I N G YO U C U R R E N T S I N C E 1 9 7 7 • w w w. p h a r m te c h .co m
Excipient GMP
The American National

Standard for Excipient GMP
Impact on the Manufacturer
Irwin Silverstein
B
The author reviews significant changes to GMP for etween September 2010 and December 2011, a joint
excipients in the forthcoming American National committee organized by NSF International worked
Standard, including a risk-based approach to to complete a draft of NSF 363, a new American
National Standard for excipient GMP. The draft
excipient manufacture, why new requirements
standard, Good Manufacturing Practices (GMP) for Phar-
were proposed, and their potential impact to maceutical Excipients, has completed the public comment
excipient manufacturers. 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 standard

NSF 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
Irwin Silverstein, PhD, is vice-president and chief operating that federal agencies adopt private-sector standards, par-
officer at International Pharmaceutical Excipients Auditing, ticularly those developed by standards-developing organiza-
1655 N. Fort Myer Drive, Suite 700, Arlington, VA 22209, tions, wherever possible, in lieu of creating proprietary, non-
tel. 703.351.5266.
consensus standards. Further, the US Office of Management
and Budget’s Circular A119 provides for “Federal Participa- the purpose of the article, quality is taken to mean consis-
tion in the Development and Use of Voluntary Consensus tent excipient composition and freedom from contamina-
Standards and in Conformity Assessment Activities.” As a tion. Risk assessment is defined in NSF 363 as “a systematic
result, FDA may adopt the ANSI standard GMP regulations process of organizing information to support a risk decision
for excipient ingredients manufactured for use in pharma- to be made within a risk management process. It consists of
ceutical dosage forms intended for US domestic markets. the identification of hazards and the analysis and evaluation
The NSF joint committee organized to prepare the excipi- of risks associated with exposure to those hazards” (1). (For
ent GMP standard, designated as NSF 363, is comprised of details on conducting and documenting risk assessments as
representatives of excipient manufacturers, pharmaceutical required by the standard, please see the article “Conducting
users, and the general interests of the industry, including Risk Assessment in Support of ANSI Excipient GMPs” in
FDA, academia, and public health organizations. The final this issue.) The IPEC–PQG excipient GMP guide, as well
draft of NSF 363 was completed in the fourth quarter 2011 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
A key challenge was to develop assure control measures are commensurate with those risks
(1). Several sections and clauses of the new standard are ex-
excipient GMPs that would plained below. Note that the term “Section” as used in this
article refers to requirements that also contain enumerated
be applicable to the diverse subordinate requirements referred to herein as “Clauses.”
The first clause in NSF 363 to refer to risk is 4.2.1 (Quality
operational activities of the Management System/ Documentation Requirements/Gen-
excipient industry. 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
and was made available for public comment at the end of the quality of the excipient across its life cycle, are to be used to
year. The 45-day public comment period ended in January evaluate changes to the quality management system. Such
2012, and the NSF joint committee reviewed the comments changes include activities, operations, and processes that
to the draft standard. Revisions to NSF 363 are in progress pose a risk to excipient quality. Also in this clause is the re-
with final approval of the standard is expected to occur in quirement to document a risk assessment that justifies those
the second quarter of 2012. Following the joint committee’s other clauses of the standard that do not apply to excipient
approval, the standard will be considered by NSF’s Council manufacture and are thus not implemented.
of Public Health Consultants with final approval by ANSI’s Section 4.3 on Quality Management System/Change Con-
Board of Standards Review. If approved as expected, the trol requires the implementation of risk assessment as a tool to
standard will be published by the end of 2012. determine the impact of change involving the manufacture of
the excipient. Here, IPEC–Americas has provided a guide as
New excipient GMP requirements a basis for conducting the risk assessment. Any change that
Excipients come from a broad range of the chemical- and may impact the consistent composition or performance of the
food-ingredient industries. Inorganic excipients usually excipient should be considered potentially significant and the
begin with the mining of minerals. Excipients whose start- pharmaceutical customer should be notified as suggested in the
ing material is grown on a farm or forest are often further IPEC guide for significant change reporting (4).
processed into a derivative through chemical reaction or Section 6 on Resource Management requires several risk
fermentation. Synthetic excipients can be produced at the assessments to identify the potential for contamination of
manufacturing site from basic chemical starting materials, the excipient. For example:
such as ethylene and acetylene. The one process common to • Clause 6.2.3 (Human Resources/Hygienic Practices)
all excipient manufacturing is purification of the material describes risk assessment to identify the potential for
to meet the requirements of a pharmaceutical ingredient. contamination of the excipient by personnel and/or
A key challenge of the NSF joint committee, therefore, was their activities. Where a risk to the excipient exists, the
to develop excipient GMPs that would be applicable to the standard provides five measures that may be taken to
diverse operational activities of the excipient industry. minimize said risk. The proposed control measures will
Risk assessment. NSF 363 represents the evolution of the be familiar to manufacturers who have implemented
joint IPEC–PQG GMP for Pharmaceutical Excipients (2) excipient GMPs as noted in the IPEC–PQG guide (2).
into an American National Standard suitable for regulation • Clause 6.3.1 (Infrastructure/Buildings and Facilities)
by FDA. The most significant new requirement in NSF 363 requires risk assessment to evaluate the threat to ex-
not found in the joint IPEC–PQG guide involves the use of cipient contamination posed by the buildings and facili-
risk management to ensure consistent excipient quality. For ties. This assessment is to consider the intended use of
Excipient GMP
the excipient (i.e., oral, parenteral, topical applications, documented. Informal assessment of risk to excipient qual-
etc.). The five aspects presented for consideration are ity has always been an expectation in IPEC excipient GMP
discussed in the IPEC–PQG guide (2). The provision guides however.
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 The provisions for risk
from the manufacturing facility.
• Clause 6.3.3 (Utilities) stipulates evaluation of contami- assessment in NSF 363 are
nation risk from utilities but does not require linkage to
the intended use of the excipient.
new in that they are to be
• Section 6.4 on Work Environment requires the assess- formally conducted and
ment of contamination risk from exposure to the work
environment. This risk assessment is linked to customer documented.
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- Other noteworthy requirements. Several other provisions in
mentation of conformance to the control measures imple- NSF 363 are either new to excipient GMP requirements or
mented to address the risk to excipient quality noted in the differ from that suggested in the IPEC–PQG Excipient GMP
assessment. However, Clause 6.4.4 (Pest Control) provides guide (2). In particular, the excipient manufacturer should
for a risk assessment to identify the elements needed in a be aware of the following differences.
pest control program. Clause 4.2.4 (Quality Management System/Documenta-
Section 7 on Excipient Realization, further provides for tion Requirements/Control of Records) requires that records
risk assessments, as follows: be kept for 1 year beyond the excipient expiration date or
• Clause 7.4.1 (Purchasing/Purchasing Process) requires first re-evaluation date. The standard further states that
the identification of quality-critical materials and ser- where the manufacturer does not stipulate a re-evaluation
vices through risk assessment. The requirements of this or expiration date, the records should be retained for five
clause are applicable only to those materials and ser- years. The IPEC-PQG Excipient GMP guide merely suggests
vices identified as quality-critical, except for the gen- keeping records for a defined period.
eral expectation to have an agreed specification from Specified responsibilities of an independent Quality Unit
approved suppliers. While neither the standard nor the are noted in Clause 5.5.1 (Management Responsibility/Re-
IPEC–PQG Excipient GMP guide provide criteria for sponsibility, Authority, and Communication/Responsibil-
the determination as to whether a material or service is ity and Authority) with allowance to delegate some duties.
quality-critical, the assessment should be based on the While these responsibilities are also listed in the IPEC–
potential impact to excipient quality (2). The suppliers PQG Excipient GMP guide as is allowance for delegation,
of quality critical raw materials should be expected to the standard further notes that ultimate responsibility for
notify the manufacturer of a process change so that the oversight and approval remains with the Quality Unit.
excipient manufacturer can evaluate the change for the As noted, Clause 7.4.1 (Purchasing Process) requires the
potential impact to the excipient. identification of quality-critical materials and services.
• Clause 7.5.5.1 (Production and Service Provision/Pres- However, unlike the IPEC–PQG Excipient GMP guide, the
ervation of Product/Raw Material Packaging Systems) standard specifically includes packaging materials. Also
requires a risk assessment to assure the storage and where the guide notes that periodic audits may be required,
handling of raw materials provides suitable protection the standard notes the assessments are to be ongoing. The
against deterioration or contamination and that iden- expectation of the standard is for the manufacturer to con-
tification labels remain legible. tinuously monitor the conformance of these suppliers to the
• Clause 7.5.5.2 (Production and Service Provision/Pres- purchasing agreement.
ervation of Product/Excipient Packaging Systems) pro- Clause 7.4.3 (Purchasing/Verification of Purchased Prod-
vides for a risk assessment only where reusable contain- uct) adds several new requirements:
ers are returned for further use. • Justification for not sampling any incoming material
The only requirement for risk assessment in Section 8, • Verification of the measurements reported on the sup-
Measurement, Analysis and Improvement, is in clause 8.3.2 plier Certificate of Analysis (COA)
(Control of Nonconforming Product/Reworking). Here, a • Verification that the Certificate of Conformance for
risk assessment is required to assess the risk of the rework packaging components references the current agreed
operation to excipient quality. specification.
In conclusion, the provisions for risk assessment in NSF Section 7.5 on Production and Service Provision, also
363 are new in that they are to be formally conducted and contains several new provisions:
• Requirements for equipment and utensil cleaning and Conclusion
sanitization are expanded under clause 7.5.1 (Control This article highlights the new requirements for excipient GMP
of Production and Service Provision). In addition to the as reflected in NSF 363. It expresses the opinion of the author as
expectations noted in the IPEC–PQG guide, the stan- to what requirements in the draft ANSI excipient GMP standard
dard requires the establishment of criteria to confirm differ from the IPEC–PQG Excipient GMP Guide. It is important
cleaning effectiveness, requires chronological records to note that at the time this article was prepared, the public com-
of cleaning activities and identification of the cleaning ment period for the standard had just been completed. Based upon
status of equipment. input, requirements as described here may be modified. The reader
• There is a requirement to demonstrate ongoing evidence is thus urged to review the requirements in the approved NSF 363
of process capability under Clause 7.5.2 (Validation of standard for applicability to their manufacturing operation. While
Processes for Production and Service Provision). certain new requirements are expressed in the standard, they ei-
• Clause 7.5.3 (Identification and Traceability) stipulates ther evolved from implied expectations in the excipient GMP
documentation that defines identification and trace- guide or are enhancements resulting from the current business
ability for raw materials in continuous processing. The and regulatory climate. NSF 363 is organized in accordance with
IPEC-PQG guide suggests using the time material was ISO 9001 but adds new clauses where appropriate. The organiza-
processed for traceability. This clause also requires that tion of this American National Standard will facilitate submission
labeling include the manufacturing address or a refer- of the standard to ISO for their adoption as a global standard.
ence to the site of manufacture.
• Under Section 7.5.5 on Preservation of Product, the References
manufacturer is expected to justify the handling and 1. NSF Joint Committee, Draft Good Manufacturing Practices (GMP)
storage conditions for quality critical materials. for Pharmaceutical Excipients (2012).
• Where excipient is shipped in bulk, there is to be a list of 2. IPEC–PQG, Joint IPEC–PQG Good Manufacturing Practices
restricted or allowed previous cargoes for non-dedicated Guide for Pharmaceutical Excipients (2006).
bulk transport equipment according to Clause 7.5.5.3 3. ANSI, Essential Requirements: Due Process Requirements for
(Excipient Delivery). American National Standards.
Section 7.6, Control of Monitoring and Measuring Equip- 4. IPEC–Americas, Significant Change Guide for Bulk Pharmaceuti-
ment, describes the expectations for measuring and test de- cal Excipients (2009).
vices used to make quality-critical measurements. 5. IPEC–Americas, Certificate of Analysis Guide for Bulk Pharma-
There are several new expectations under Section 8.2.4, ceutical Excipients (2000). PT
Monitoring and Measurement of Product:
• Clause 8.2.4.1.1 (Laboratory Controls) adds the require-
ment to provide documentation of sample preparation * Call for Papers* Call for Papers * Call for Papers *
to show conformance with the test method. In addition Pharmaceutical Technology welcomes manuscripts about
there is a requirement to reference the test method. This
subjects pertinent to all aspects of applied research and
documentation will facilitate the investigation of Out-
of-Specification test results. development, scale up, and manufacturing technologies for
• Clause 8.2.4.1.2 (Laboratory Procedures) notes that re- the pharmaceutical industry. Topics include regulatory affairs,
agents and test solutions are to have expiration or re- contract services, drug-delivery systems, ingredients, formulation,
standardization dates. analytical methods and testing, information technology,
• Clause 8.2.4.5 (Certificate of Analysis) includes the pro-
vision noted in the IPEC–Americas COA guide to in- processing, packaging, validation, and API synthesis.
clude the “manufacturer’s name and site of manufacture All papers undergo a double-blind peer-review process by
or reference to the site of manufacture” (5). members of the Pharmaceutical Technology Editorial
Section 8.3 on Control of Nonconforming Product, adds Advisory Board to determine whether they are appropriate for
a couple of requirements:
publication. Before they undergo peer-review, papers are first
• Nonconformance is to be investigated to identify the
root cause and potential impact to other batches or reviewed by the senior editorial staff.
products. Pharmaceutical Technology also publishes special focused issues
• Under Clause 8.3.2 (Reworking) customers are to be each year featuring case studies, best practice and tutorial articles,
notified if they are provided with a reworked batch. Such and literature reviews. Upcoming topics include:
material represents a potential significant change since
routine processing was not followed.
Sterile Manufacturing, Ingredients, and Analytical Testing.
The last addition of note is in Section 8.4 on Analysis of Data, Author guidelines can be found online,
which requires monitoring of nonconformance with this stan- at PharmTech.com under “For Authors.”
dard and of supplier nonconformance are new requirements.
Risk Assessment, Excipients
Standardized Excipient GMP

Conducting a Risk Assessment
Dale Carter
T
he forthcoming American National Standard
ThomAs NorThCuT/GETTy ImAGEs
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
This article provides guidance for industry on manufacturing processes, their raw-material sources,
how to comply with the pending American their chemical and physical properties, and their many
National Standard on excipient GMP, with a end users in different types of drug products. Attempts
to define requirements in such areas as personnel hy-
focus on risk assessment.
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

Dale Carter is chair of the International Pharmaceutical NSF 363 requires risk assessments to support decisions and
Excipient Council of the Americas (IPEC–Americas). implement controls (see Tables I–IV). For example, Section
4.2.1 on Documentation requires incorporating quality

process should be commensurate with
Table I: NSF 363 sections requiring a risk assessment (Ref 1). the level of risk” (3).
These principles can help to frame a
Sect. # Title Requirement company’s thought process when con-
ducting and documenting risk assess-
…a documented risk assessment that
ment by focusing the activity on the
Documentation defines and justifies when the as/if/where
4.2.1 d overall goal of protecting the patient.
requirements, General applicable clauses in this standard are not
implemented
The principles direct the industry to
use science when determining the sig-
To protect excipients from contamination, nificance “of the probability of occur-
the organization shall conduct a risk rence of harm and the severity of that
6.2.3 hygienic Practices assessment to identify areas where the harm” (1). It is also pointed out that
excipient is at risk of contamination from
not all risks are equal, and therefore,
personnel and/or their activities.
each documented risk assessment may
The organization shall conduct a risk or may not provide the same level of
assessment based on the organization’s detail or supporting data.
expressed, intended use of the excipient NSF 363 adopts the same definition
6.3.1 Buildings and facilities (see 7.2.3) to identify areas in which the for risk assessment as found in ICH
excipient is at risk of contamination or mix-
Q9, namely: “a systematic process of
ups due to deficiencies in buildings and/or
organizing information to support a
facilities.
risk decision to be made within a risk
The organization shall conduct a risk management process. It consists of the
assessment considering the risk to identification of hazards and the anal-
6.3.3 utilities excipient quality from utilities (nitrogen, ysis and evaluation of risks associated
compressed air, steam, etc.) used in the with exposure to those hazards” (3).
production, storage, or transfer of materials.
In Q9, a hazard is a potential source of
The organization shall conduct a risk harm and harm is “damage to health,
assessment to identify areas in which the including the damage that can occur
6.4 Work Environment
excipient is at risk for contamination from from loss of product quality or avail-
exposure to the work environment. ability” (3). This definition highlights
If an agreement cannot be obtained, a
the difference between risk assess-
risk assessment must be performed and a ment for excipients and hazard anal-
7.4.1 Purchasing Process ysis for food ingredients. In Hazard
written justification for continued use of the
supplier shall be available. Analysis and Critical Control Points
(HACCP) plans used throughout the
Where reusable excipient containers are
food industry, the focus lies on pre-
Excipient Packaging returned, the organization shall undertake a
7.5.5.2
systems risk assessment and establish appropriate
venting microbiological, chemical, or
controls for their further use. physical contamination that is reason-
ably likely to cause illness or injury.
reworking excipient is a change under No consideration is given to consis-
the provisions of change control in this tency of composition or functionality
standard (see 4.3) and shall only be
8.3.2 reworking of the ingredient. Excipient manu-
conducted following a documented review
facturers must assess the impact of a
of risk to excipient quality that is approved
by the quality unit.
change to excipient composition on its
functionality and performance in the
drug product, but only the user of the
risk-management principles into changes to the quality- excipient can adequately make this assessment. The excipi-
management system (1). The International Conference on ent manufacturer understands the range of variability, in
Harmonization (ICH) Q9 Quality Risk Management guide- chemical composition and physical properties, of its prod-
line, a reference document for NSF 363, gives two primary uct and may communicate this to the user during quali-
principles: “The evaluation of the risk to quality should be fication. The excipient manufacturer is expected to use
based on scientific knowledge and ultimately link to the risk assessment to prevent deviations in the stated range
protection of the patient” and “the level of effort, formal- of variability. For this reason, the excipient manufacturer’s
ity, and documentation of the quality risk management documentation of its product’s composition and variability

the basis for determining appro-
Table II: NSF 363 sections requiring justification (Ref. 1). priate risk control. The sections of
NSF 363 requiring risk assessment
Sect. # Title Requirement preload the process by defining the
scope or risk question, providing the
…justification of the processing step from
4.2.2 d Quality manual nature of hazards to be considered,
which point this standard shall be applied
and pointing to risk controls that
The Quality unit may delegate some should be implemented. The docu-
aspects of these activities if justified as mentation necessary to demonstrate
responsibility and appropriate, however, they shall retain conformance to the standard should
5.5.1
Authority ultimate responsibility for oversight facilitate assessment of the results in
and approval of all delegated activities,
terms of the risks to be controlled,
applicable controls, and final decisions.
the reasoning and facts leading to
The organization shall justify any material the conclusions, understanding the
Verification of Purchased not sampled prior to approval and release, risks that were considered, and pro-
7.4.3
Product such as when the material is too hazardous vides evidence that competent people
or toxic to sample and test. equipped with adequate information
…equipment and utensil cleaning and followed a process that ensured a
sanitization procedures justifying the complete assessment. The actual pro-
method and frequency of cleaning, cess for conducting a risk assessment
Control of Production and establishing criteria for determining may vary depending on the scope of
7.5.1 b
service Provision effectiveness, and requiring chronological the exercise but the documentation,
records of cleaning activities as noted except where risk are either obvious
above; the cleaning status of equipment or cannot possibly exist, should in-
shall be known, clude (4):
The organization shall define and justify • Objective and scope of assessment
the conditions for the handling and storage • Team members and their support-
of quality-critical materials (see 7.5.3) so ing qualifications (e.g., technical
7.5.5 Preservation of Product
their identity, quality, and conformance to expertise and/or training in con-
specification are not affected within their ducting risk assessment)
shelf life or re-evaluation period. • Description, diagram, or f low
chart of what was included
• Supporting references and infor-
Table III: NSF 363 sections requiring decisions based on risk assessment (Ref. 1). mation relating to the assessment,
including policies and procedures
Sect. # Title Requirement • Assessment methodology
• Risk identification results
The Quality unit shall approve any changes • Data, assumptions, and their
4.3 Change Control that based on risk assessment may impact
sources and validation
the quality of the excipient.
• Risk analysis results and evaluation
Based on risk assessment, top • Risk criteria applied and justifi-
management shall be notified in a timely cation
5.5.3 Internal Communication
manner of events that affect excipient • Limitations, assumptions, and
quality and shall support appropriate justification of hypotheses
corrective and preventive actions, in
• Critical assumptions and other fac-
accordance with a documented procedure.
tors which need to be monitored
• Discussion of results
provides crucial information for conducting an adequate • Conclusions and recommendations or reference to result-
risk assessment. This information is also a requirement ing controls.
of NSF 363 Section 8.2.4.6 on Excipient Composition (1). As with all records, this documentation should be
maintained and be available for audit as well as for use in
Documenting a risk assessment periodic review of the assessment to ensure its continuing
Risk assessment consists of risk identification, risk validity and suitability in the presence of new informa-
analysis, and risk evaluation with the output forming tion. Including a summary and reference to the risk as-

into a common exercise and risk-
assessment report. The report may
Table IV: NSF 363 sections requiring risk controls as a result of risk begin with a summary of the risk-
assessment (Ref. 1). assessment results and supporting
Sect. # Title Requirement arguments. The common supporting
documentation would be included in
Where the risk assessment has identified the body or an appendix. Supporting
that an air handling system poses a documentation includes items such as
potential risk to excipient quality, the air
6.4.1 Air handling a description of the product with back-
handling system shall be designed and
ground information such as:
maintained to assure adequate protection
of the excipient.
• Support for excipient stability
• Susceptibility for growth of mi-
Where the risk assessment has identified croorganism and other charac-
the need for a controlled environment, teristics
6.4.2 Controlled Environment
it shall be monitored to assure excipient • Product’s intended use
quality.
• Description of the process and
Where the risk assessment (see 6.3.1) a f low diagram showing all unit
has identified that clean and/or sanitary operations, inputs, and recycle
Cleaning and sanitary
conditions of the work environment are streams
6.4.3
Conditions
necessary to protect excipient quality, the • List of team members participat-
organization shall document procedures ing in the risk assessment with a
assigning responsibility for cleaning and/or description of their qualifications
sanitation.
to perform such a task.
The elements of the pest control program A clear statement supporting the ex-
6.4.4 Pest Control
shall be determined by risk assessment. cipients unique chemical and physical
characteristics and any unique pro-
Based on the results of the risk assessment
6.4.7
Washing and Toilet
in 6.2.3, facilities for showering and/or
cessing conditions or equipment will
Facilities help justify the exclusion or inclusion
changing clothes shall be provided.
of potential hazards. For example, a
Where a risk assessment has demonstrated low pH can be used to justify the ab-
that storage and handling of raw materials sence for specific controls to prevent
may impact excipient quality, the
microbiological contamination.
organization shall:
Documentation should demon-
raw material Packaging a) provide suitable protection against
7.5.5.1
systems deterioration, contamination with
strate that the risk assessments re-
foreign substances, chemical and/or quired in NSF 363 Section 6 were
microbiological contamination, and performed for all unit operations. A
b) ensure that identification labels remain matrix table can be included docu-
legible. menting the process f low, unit op-
erations, and production and storage
areas in rows with columns listing
sessment reports in the quality manual helps describe the potential hazards and the justification for suitable con-
quality management system and aids in understanding the trols (or controls being unnecessary) to protect against
basis for controls included as part of the GMPs. To pre- such risks as: contamination from personnel and/or their
vent the loss of a company’s knowledge base, training and activities; contamination or mix-ups due to deficiencies
familiarization with the content of the risk-assessment in buildings or facilities; deterioration of excipient qual-
documents should be included as part of succession plan- ity from contact with utilities; and contamination from
ning, personnel development or job descriptions for key exposure to the work environment. Reference to the sup-
positions where appropriate. porting documentation (including a statement of how the
process flow was verified for accuracy and inclusion of all
Conducting a risk assessment operations) should accompany the table.
Conducting and documenting a risk assessment of the manu- The risk-assessment process for determining signifi-
facturing process as directed in the NSF 363 Section 6 6.2.3 cant change as a part of change control is discussed in the
on Hygienic Practices, 6.3.1 on Buildings and Facilities, 6.3.3 IPEC–Americas Significant Change Guide (5). A key point
on Utilities, and 6.4 on Work Environment can be combined from this guide is that, “Any change by the manufacturer

of an excipient that [may] alter an excipient physical or (2): “An activity that is not a normal part of the manu-
chemical property outside the limits of normal variability, facturing process (reworking) should only be conducted
or that is likely to alter the excipient performance in the following a documented review of risk to excipient quality
dosage form is considered significant.” The level of sig- and approval by the quality unit. As appropriate, when
nificance depends on the type of change and is evaluated performing the risk assessment, consideration should be
according to seven criteria: given to…..”
1. Will there be a change in the chemical properties of The procedures and controls associated with the
the excipient as a result of the change? IPEC–PQG GMPs have always been the output of risk-
2. Will there be a change in the physical properties of assessment exercises. NSF 363 takes this concept fur-
the excipient as a result of the change? ther to justify the thought process used to support and
3. Will there be a change in the impurity (composition) document controls are. Such documentation facilitates
profile for the excipient as a result of the change? better understanding of GMP controls across excipient
4. Will there be a change in the functionality of the ex- manufacture.
cipient as a result of the change?
5. Where applicable, will the moisture level changed? References
6. Where applicable, will the bioburden changed? 1. NSF Joint Committee, Draft Good Manufacturing Practices
7. Will there be a change in the origin of any raw materi- (GMP) for Pharmaceutical Excipients (2012).
als or contact packaging? 2. IPEC–PQG, Joint IPEC–QG Good Manufacturing Practices
These criteria can be used in a change-control program Guide for Pharmaceutical Excipients (2006).
and should be referenced in the documentation to comply 3. ICH, Q9 Quality Risk Management (2006).
with NSF 363 Section 4.3 on Change Control. 4. IEC/ISO 31010, Section 5.5, Risk Management–Risk Assessment
The requirements to perform documented risk as- Techniques, 1.0 (2009-2011).
sessments in support of GMP controls are not entirely 5. IPEC–Americas, Significant Change Guide for Bulk Pharmaceuti-
new. Section 8.3.2 of the IPEC–PQG GMP guide states cal Excipients (2009). PT
Ad Index
COMPANY 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

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