Unlocking the Vast Potential of Process Analytical...

JUNE 2015 Volume 27 Number 6

Unlocking the Vast Potential of

Process Analytical Technology

REGULATORY WATCH

EU’s Variations Framework

BIOPHARMACEUTICALS

Top Trends in Biopharma

FORMULATION

Dry Powder Inhalers

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Cover: PASIEKA/Getty ImagesArt direction: Dan Ward

PTE magazine is audited

by the BPA

June 2015

Features

COVER STORY

14 Unlocking the Vast Potential of

PAT in Solid-Dosage Manufacturing

PAT holds the key to real-time quality assurance

and consistent product quality in pharmaceutical

manufacturing.

BIOPHARMACEUTICAL MANUFACTURING

20 Top Trends in Biopharmaceutical Manufacturing

New cell-culture techniques, biomanufacturing formats,

types of biological products, and the expansion of

single-use applications are driving rapid change in the

biopharmaceutical market.

FORMULATION

26 Developing an Orally Inhaled Dry Powder

Formulation—A Complex Itinerary and

a Technological Challenge

Successful drug delivery via a dry-powder inhaler is

determined by factors such as the API physicochemical

properties, the formulation composition and

process, the device and its operating conditions,

as well as the patient-device relationship among others.

FACILITIES

29 Designing Clean Zones

Clearly defined zones of cleanliness

help prevent product contamination.

PharmTech.com

Regulars5 Editor’s Comment

A Growing Appetite for Vaccines

6 Product Spotlight

8 Outsourcing Review

Another In-house Operation Gets Outsourced

12 EU Regulatory Watch

EU’s New Post-Authorization Variations

Framework Comes Under Scrutiny

41 API Synthesis & Manufacturing

New Ways Around Hazardous Reagent Chemistry

43 Product/Service Profiles

49 Troubleshooting

Preventing Common Mistakes in Automated Washing

50 Ad Index

Peer-Reviewed31 Using a Dual-Drug Resinate

Complex for Taste Masking

Box–Behnken modelling was used to optimize a

resinate complex to mask the taste of levocetirizine

dihydrochloride and montelukast sodium in orally

disintegrating tablets.

Join PTE’s communityJoin the Pharmaceutical Technology europe group on LinkedIn™*

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26 2920 14

Pharmaceutical Technology europe is the authoritative

source of peer-reviewed research and expert analyses for

scientists, engineers, and managers engaged in process

development, manufacturing, formulation and drug

delivery, API synthesis, analytical technology and testing,

packaging, IT, outsourcing, and regulatory compliance

in the pharmaceutical and biotechnology industries.

Advancing Development & Manufacturing

PharmTech.com

eBookBe sure to check out PharmTech’s

BioProcessing and Sterile Manufacturing

eBook for articles on facility planning,

elastomers, sterility testing, mAbs,

and more!

PharmTech.com

2015

BIOPROCESSING AND STERILE MANUFACTURING

e B O O K S E R I E S

Pharmaceutical Technology Europe June 2015 3

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PharmTech EuropeEditorAdeline Siew, [email protected]

PharmTech GroupEditorial DirectorRita [email protected]

Senior EditorAgnes [email protected]

Managing EditorSusan Haigney [email protected]

Manufacturing EditorJennifer [email protected]

Science EditorRandi [email protected]

Community EditorAshley [email protected]

Contributing Editor

Cynthia A. Challener, PhD

Global Correspondent

Sean Milmo

(Europe, [email protected])

Art Director

Dan Ward

Graphic Designer

Courtralingam Madasamy

Publisher

Michael Tracey

[email protected]

Associate Publisher

Chris Lawson

Tel. +44 1244 629 324

[email protected]

Senior Sales Executive

Stephen Cleland

Tel. +44 1244 629 311

[email protected]

Published byUBM Life SciencesHoneycomb West,Chester Business Park,Wrexham Road,Chester, CH4 9QH, United KingdomTel. +44 1244 629 300Fax +44 1244 678 008

UBM Life Sciences:Chief Executive OffcerJoe Loggia

Executive Vice-President, Life SciencesTom Ehardt

Executive Vice-PresidentGeorgiann DeCenzo

Executive Vice-PresidentChris DeMoulin

Executive Vice-President, Business SystemsRebecca Evangelou

Executive Vice-President, Human ResourcesJulie Molleston

Executive Vice-President, Strategy & Business DevelopmentMike Alic

Sr Vice-PresidentTracy Harris

Vice-President, General Manager Pharm/Science GroupDave Esola

Vice-President, LegalMichael Bernstein

Vice-President, Media OperationsFrancis Heid

Vice-President, Treasurer & ControllerAdele Hartwick

UBM Americas:Chief Executive OffcerSally Shankland

Chief Operating OffcerBrian Field

Chief Financial OffcerMargaret Kohler

UBM PLC:Chief Executive OffcerTim Cobbold

Group Operations DirectorAndrew Crow

Chief Financial OffcerRobert Gray

ChairmanDame Helen Alexander

Kevin Altria

Associate Director,

Pharmaceutical Development

GlaxoSmithKline R&D

Reinhard Baumfalk

Vice-President, R&D

Instrumentation & Control

Sartorius AG

Rafael Beerbohm

Head of Quality Systems

Boehringer Ingelheim GmbH

Gabriele Betz

Department of

Pharmaceutical Sciences

University of Basel, Switzerland

Phil Borman

Manager, GlaxoSmithKline

Rory Budihandojo

Director, Quality and EHS Audit

Boehringer-Ingelheim

Christopher Burgess

Managing Director

Burgess Analytical Consultancy

Ryan F. Donnelly

Reader in Pharmaceutics

Queens University Belfast

Tim Freeman

Managing Director

Freeman Technology

Filipe Gaspar

Director of Drug Product

Technology, Hovione

Sharon Grimster

General Manager

Reneuron

Anne Marie Healy

University of Dublin, Ireland

Deirdre Hurley

Senior Director, Plant

Helsinn Birex

Pharmaceuticals Ltd.

Makarand Jawadekar

Independent Consultant

Henrik Johanning

Senior Vice-President,

Compliance, QAtor A/S

Marina Levina

Product Owner-OSD, TTC-

Tablets Technology Cell, GMS

GlaxoSmithKline

Roberto Margarita

Business Development Director

Corden Pharma

Luigi G. Martini

Chair of Pharmaceutical

Innovation

King’s College London

Thomas Menzel

Menzel Fluid Solutions AG

Jim Miller

President,PharmSource

Information Services

Colin Minchom

Vice-President, Particle Design

Hovione

Clifford S. Mintz

President and Founder

BioInsights

Ian Pearson

Senior Design Team Leader,

TSL Projects

Tim Peterson

Transdermal Product

Development Leader, Drug

Delivery Systems Division, 3M

John Pritchard

Technical Director

Philips Respironics

Thomas Rades

Professor, Research Chair in

Formulation Desgin and Drug De-

livery, University of Copenhagen

Jean Paul Remon

Ghent University, Belgium

Rodolfo Romañach

Professor of Chemistry

University of Puerto Rico,

Puerto Rico

Beatriz San Martin

Senior Associate

Field Fisher Waterhouse LLP

Siegfried Schmitt

Principal Consultant

PAREXEL

Stane Srcic

Professor

University of Ljubljana, Slovenia

Griet Van Vaerenbergh

GEA Process Engineering

Benoît Verjans

CEO

Arlenda

Andreas Weiler

Global Technical Sales Director

SAFC

Tony Wright

CEO

Exelsius

EDITORIAL ADVISORY BOARD

Above is a partial list of the Pharmaceutical Technology brand editorial advisory

members. The full board, which includes advisory members of Pharmaceutical

Technology North America, can be found online at www.PharmTech.com/EAB.

Pharmaceutical Technology publishes contributed technical articles that undergo

a rigorous, double-blind peer-review process involving members of our distin-

guished Editorial Advisory Board. Manuscripts for editorial consideration should

be sent directly to Susan Haigney, managing editor, [email protected]% PostConsumer

Waste

4 Pharmaceutical Technology Europe June 2015 PharmTech.com

Editorial: All submissions will be handled with reasonable care, but the publisher assumes no responsibility for safety of

artwork, photographs, or manuscripts. Every precaution is taken to ensure accuracy, but the publisher cannot accept

responsibility for the accuracy of information supplied herein or for any opinion expressed.

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EDITOR’S COMMENT

A Growing Appetite for Vaccines

Vaccines are fast becoming attractive

assets for the pharmaceutical industry

as their market demand continues to soar.

Today, the use of vaccines is no longer limited

to prophylaxis, or only for battling pandemics

and epidemics, but these agents now have

a place in treating chronic diseases such as

HIV/AIDS and cancer. While pharmaceutical

companies tend to have minimal reservations

investing in cancer drug development because of the higher

returns, it is a different story for HIV vaccine R&D. Investments

have been declining since 2008, such that the United Nations was

prompted to issue a call for sustained commitment in developing

an effective HIV vaccine, stating that it would be a major step

towards ending AIDS (1). After all, vaccines played their part in

eradicating small pox, with polio now close to eradication as well.

Research and consulting firm Visiongain has projected that

sales of human vaccines will multiply during the next decade,

with revenues hitting $56 billion in 2019 (2). While an aging

population worldwide has been cited as a contributing factor,

other key drivers include advances in vaccine manufacturing as

well as the promising progress seen in vaccine R&D.

It is no surprise that the industry is eager to seize this

opportunity. Pharmaceutical companies appear to be investing

mainly in the therapeutic applications of vaccines, according

to Visiongain’s report, “World Vaccines Industry and Market

2015–2025,” published in February 2015. Commenting on the

report, Bochung Lam, healthcare industry analyst at Visiongain,

pointed out that a number of disorders lack a definitive form of

treatment, resulting in sufferers being left untreated. This is an

area where vaccines can offer a solution, he noted.

The overall future looks bright for vaccine development

with technological advances paving the way to innovative

vaccine formulations and improved methods of storing these

drug products. Lam, however, cautioned that “regulations and

other governmental demands will form a challenge to vaccine

developers, manufacturers, and marketers from 2015 to 2025.”

Adeline Siew, PhD

Editor of Pharmaceutical Technology europe

[email protected]

References

1. UNAIDS, “unAIDS calls for sustained commitment to develop

an effective HIV vaccine,” Press Release, 18 May 2015.

2. Visiongain, “World Vaccines Industry and Market 2015–2025,”

February 2015.

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6 Pharmaceutical Technology Europe JUNE 2015 PharmTech.com

PRODUCT SPOTLIGHT

DPI Lab Mixer Increases EfficiencyHosokawa MicronÕs Mini

Cyclomix lab mixer is

designed to blend

formulations for dry-

powder inhalers (DPIs)

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particles. The mixer

features exchangeable

product bowl sizes of

100 mL, 1 L, and 2 L, which

require no special tools to

be connected to the drive unit with a bayonet ring.

An integrated touch panel operates the unit, with recipe

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mixing speed and time allows the mixer to be used for coating,

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When the rotational movement moves the product to the top of the

vessel, a formed dome at the top of the mixer pushes the product

back down through the center of the vessel, ensuring a thorough

mixing process.

Hosokawa Micron

www.hosokawa.co.uk

Four-Axis Robot Eliminates the Need for Manual Drift CorrectionThermo ScientificÕs Spinnaker

Smart Laboratory Robot,

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compensating for positional variations. The learning robot features

built-in vision, which can be used as a bar code reader for

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The systemÕs four-axis SCARA, or Òselective compliance

articulated robot arm,Ó increases the automatic workflow.

Positioning can be achieved during teaching or integrating

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variety of third-party instruments and peripherals.

Thermo Scientific

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Conical Tube Reduces Contamination Risk

EppendorfÕs Conical screw

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The tubes are designed

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Eppendorf

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Ross Multi-Shaft Mixer Reduces Changeover TimeRossÕ Multi-Shaft Mixers

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One of the mixers, a

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The mixer is designed so the user can easily remove the vessel

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Quick acting clamps secure the holding tank cover, which is

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Ross, Charles & Son Company

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OUTSOURCING REVIEW

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A number of recent workforce surveys have shown

that professional workers are continuing to put

in longer hours. The Great Recession is partly to

blame; professional workers were laid off, and those

remaining today continue to do the work of two or

more. But as the global economy has improved, the

number of employees has not. Therefore, to get

the needed productivity, outsourcing is becoming a

standard strategy.

Biopharmaceutical manufacturers already

outsource plenty of activities, and they’re clearly

indicating this trend is not likely to be reversed.

According to BioPlan Associates 12th Annual Report

and Survey of Biopharmaceutical Manufacturing

Capacity and Production (1), the push to outsource

is being institutionalized. Non-core functions, such

as assay testing, are a bellwether. Once again, the

industry has voted this activity the most likely to be

dumped.

Each year, BioPlan’s survey brings in more than

200 qualified biopharmaceutical manufacturers

who share their perspectives on market trends and

opportunities. Back in 2012, the survey showed a

large jump in the share of survey respondents who

projected significantly greater levels of outsourcing

of bioassay testing. Since then, this has consistently

ranked as the top area of projected outsourcing

increases.

In the 2015 survey, however, bioassay

testing stands out relative to 24 other common

bioprocessing activities. Indeed, when respondents

were asked which activities will be outsourced at

significantly higher levels at their facility during

the next 24 months, 40.9% of the industry cited

“analytical testing: other bioassays.” This percentage

was double the share of respondents indicating

they expect greater levels of fill/finish outsourcing

(19.7%), the next highest activity in terms of future

outsourcing growth. Beyond assay testing and fill/

finish, other activities in the top five for future

outsourcing activity include downstream process

development, validation services, and API biologics

manufacturing (see Figure 1).

Furthermore, of the 10 most popular activities

projected for future outsourcing growth, only three

were cited by a higher share of respondents in 2015

compared to 2014. Aside from bioassay testing

(40.9% vs. 33.9% in 2014), the others were cell-line

development and upstream process development,

each with only slight increases. In other words,

while enthusiasm for outsourcing appears to have

flattened out for most activities, it’s still going strong

for analytical testing of bioassays.

Most likely, this may be the result of continued

outsourcing of analytical methods based on the

need to have costly, high-maintenance equipment in

almost constant operation, as well as the need for

specialized staff able to run the assays and prepare

the requisite regulatory filings, which may occur only

intermittently.

US vs. European outsourcing of assaysStaffing requirements may be a larger influence in

Europe than in the United States. In the 2014 study,

Western European respondents were twice as likely

as US respondents to report difficulties in hiring high-

tech assay staff (15.8% vs. 7.3%) at their facilities.

Perhaps it’s not a coincidence that in the 2015 survey,

European respondents were particularly enthusiastic

about future outsourcing of assay testing, at almost

four times the rate of any other activity. While this

activity was also projected for future increases by

the largest proportion of US respondents, it didn’t

distance itself from the pack at nearly the same level.

Future increases in outsourcing of assay testing

may also be due to most companies currently

only outsourcing this activity to a minor degree

(see Figure 2). While assay testing is again the

most commonly outsourced activity, it tends to

be outsourced at fairly low levels in relation to

other activities. A look at the five most commonly

outsourced activities reveals that:

Another In-house Operation Gets OutsourcedBiopharma companies on both sides of the Atlantic

ship more of their assay testing to outside service providers.

OUTSOURCING REVIEW

Eric Langer is president

of BioPlan Associates,

tel. +1.301.921.5979, elanger

@bioplanassociates.com,

and a periodic contributor

to Outsourcing Review.




Outsourcing Review

• Approximately 86% of respondents

are outsourcing analytical testing

of other bioassays to some degree,

and an average of 27% of these

operations are outsourced

• 73% are outsourcing validation

services, with an average of 18% of

this activity being outsourced

• An equal 73% are outsourcing

some fill/finish services, but with

these respondents estimating

outsourcing an average of 35% of

these operations overall

• Some 72% outsource toxicity

testing, for an average of 26%

outsourced.

These results indicate that while

toxicity testing is a less commonly

outsourced activity, it is outsourced

on average to almost the same

degree as assay testing. Meanwhile,

more than one-third of facilities’ fill/

finish operations are currently being

outsourced, despite nearly three-

quarters outsourcing this activity to

some degree.

As such, the increase in future

assay testing outsourcing may be the

result of those already outsourcing

this activity planning to do so at

higher levels in the future.

Trends in other outsourcing activitiesThe BioPlan survey shows that the

popularity of some outsourcing

activities has flattened out, a

fairly understandable result given

the extent of growth witnessed

in recent years. Some notable

declines in terms of outsourcing

popularity include toxicity testing

(72% outsourcing to some degree,

down from 87% in 2014) and fill-finish

operations (73%, down from 80%

in 2014). Still, higher proportions

of respondents this year reported

having outsourced activities

including:

• contract research–laboratory (66%,

up from 59%)

• project management services

(52%, up from 43%)

• downstream process development

(41%, up from 36%).

In terms of outsourcing levels,

most activities appear to be

outsourced to a slightly lesser

degree in 2015, with the only

standouts in terms of decreased

levels being toxicity testing (26.1%

of these activities on average being

outsourced, down from 35.4%) and

cell-line stability testing (13.4%

on average, down from 19.6%).

Nevertheless, for the most part,

reported levels of outsourcing are in

the range set in prior years.

Additionally, it is expected that

the slight dip in levels of validation

services being outsourced will

be temporary, as the increasing

penetration of single-use devices

will likely spur more spending

in this area. Finally, while more

respondents are outsourcing design

of experiments (DoE), this activity is

being outsourcing to a lesser overall

degree, suggesting that companies

newly outsourcing this quality

activity are testing the waters.

ConclusionAlthough survey results suggest that

the market growth for outsourcing

of certain activities is flattening, the

overall outsourcing market appears

to be healthy, as many respondents

predict spending increases to come.

In fact, a slight majority forecast

some level of spending increase,

though most of those will be

limiting their increases to less than

25%. Overall, it is estimated that

spending on outsourcing of R&D and

manufacturing will grow by 13% in

2015; this is a healthy growth rate,

and it’s consistent with the growth in

overall biopharmaceutical sales.

While some increases in

outsourcing budgets are targeting

the more common outsourced

services, such as assay testing

and fill/finish operations, other

activities are showing increasing

importance, such as DoE and quality

by design. These activities represent

smaller budgets, so in years to

come, their growth rate may likely

be even greater than the big-ticket

outsourcing activities.

Reference1. BioPlan Associates, 12th Annual Report

and Survey of Biopharmaceutical

Manufacturing Capacity and Production

(Rockville, MD, April 2015), www.bio-

planassociates.com/12th. PTE

Figure 1: Selected activities: Future outsourcing growth.

Figure 2: Average percentage of activity outsourced.

40.9%

19.7%

16.7%

16.7%

16.7%

15.2%

Analytical testing: Other bioassays

Fill/Finish operations

API biologics manufacturing

Validation services

Downstream process development

Cell line development

Outsourcing activities projected to be done at‘signifcantly higher levels’ in future

“Which activities will be done at signifcantly higher levels

at your facility over the next 24 months?”

(Where will the greatest changes occur? - % Indicating)

Fill/Finish operations

Analytical testing: Other bioassays

Testing: Toxicity testing

Plant maintenance services

API biologics manufacturing

34.5%

27.2%

26.1%

22.4%

18.5%

Estimated average percentage of activity outsourcedby facilities

“How much outsourcing of the following activities is done by your facility today?”

(Approx percent of activity currently outsourced)

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The European UnionÕs system for post-authorization variations

has been given a major shake-up in recent years with the

help of close consultation with the pharmaceutical industry.

Companies in some pharmaceutical sectors are still trying to

adjust to the novel rules and procedures covering changes

ranging from small packaging modifications to alterations of

manufacturing processes. The legislation on the new system,

as amended in 2012, came fully into effect in August 2013 (1).

ÒThe feedback from our members is that they still need

time to adapt to the recent changes,Ó says Miriam Gargesi,

healthcare biotechnology director at the European Association

for Bioindustries (EuropaBio), Brussels, in an interview with

Pharmaceutical Technology Europe. ÒThe [new] EU system

for dealing with applications for post-authorization approvals

is very complex and still in an implementation phase.Ó

Other segments, however, particularly for generic medicines,

are pressing for yet more simplification and streamlining to

speed up the regulatory process for variations not just for

the sake of greater efficiencies but also to reduce costs.

Implications for generic medicines manufacturers

For generic medicines manufacturers and suppliers, the

regulatory costs of variations have become a major burden as

the numbers of post-marketing notifications and authorizations

have increased rapidly during the past few years, according to a

survey of its members by the European Generic and Biosimilars

Medicines Association (EGA).

The number of variations per marketing authorization each

year has gone up by approximately 45% during the past five

years, Beata Stepniewska, EGAÕs deputy director-general and

head of regulatory affairs, informs Pharmaceutical Technology

Europe. EGA also claims that the survey shows a big rise in

fees paid by companies to agencies for regulatory work on

variations. ÒBased on data gathered on an average of more

than 16,500 marketing authorizations each year over a four-year

timeframe, the variation fees per marketing authorization per

year appear to have increased by 45%,Ó adds Stepniewska.

Most generic-drug companies use the EUÕs decentralized

procedure (DCP) operated by national regulatory agencies for

variations submission. But there also appears to have been a

steep rise in variations applications through the centralized

procedure run by the European Medicines Agency (EMA). From

April 2014 to March 2015, the numbers of pre-submission

queries being handled by the agency rose from an average

of 150 per month in the first three months to approximately

200 in the last quarter, according to EMA figures (2). Despite

the increase in queries, the agency has been able to maintain

a relatively quick response time with 90% of the 2200

queries during the year receiving replies within five days.

Much of the provisions of the new system are laid down in

the EUÕs Regulation 1234/2008 (3), which was soon amended

by Regulation 712/2012 (1), mainly to clarify the process of

variation approvals by single national agencies. Also the EUÕs

pharmacovigilance legislation, as contained in directive

2010/84 (4) and which started to be implemented in 2012,

is relevant to the variations system through its article 57 (4)

on the creation of a database of details of market

authorizations. This database can provide a source of

information of minor alterations to marketing authorizations.

New groupings and worksharing schemes

The objective of the 2008 regulation (2), which replaced two

previous ones on variations approved in 2003, was to establish

Òa simpler, clearer, and more flexible legal framework while

guaranteeing the same level of public health protection,Ó

according to its preamble. It splits variations into four main

categories. Applications are to be detailed in the guidelines

that will be regularly updated, particularly as a result of

scientific and technical advances.

A type IA variation is one that has a Òminimal or no impact

at allÓ on the quality, safety, or efficacy of medicines, while

type II, which is the highest variation level, may have a

Òsignificant impact.Ó An ÒextensionÓ involves a change to an

active substance or to the strength, pharmaceutical form,

and route of administration of a medicine. Type IB variations

are those that are neither minor or major or an extension.

To ease the administrative work on changes, the regulation

introduced a system of grouping, in a single submission,

of similar or linked variations held by the same marketing

authorization holder. Variation relating to a manufacturing

process improvement, for example, can be put into a single

grouping. To avoid duplication in the regulatory work on

variations covering several marketing authorizations, a

worksharing scheme was also established under the regulation

to enable one national agency or EMA to assess similar changes

to different medicines on behalf of other national authorities.

Regulatory agencies claim that on the whole the new

groupings and worksharing schemes have made the variations

assessment procedure faster and more efficient. Ò[They]

increase efficiency by avoiding the complexity of running

parallel-related procedures and by ensuring consistency

in the assessment of the same changes across products,Ó

explains an EMA official. They also help to streamline some

specific processes, such as that for evaluating changes to

active substance master files (ASMF). ÒWorksharing of ASMF

assessments reduces the frequent updating of ASMFs and [as

a result] the regulatory burden on national authorities, ASMF

holders, and marketing authorization holders,Ó the official says.

EU’s New Post-Authorization Variations Framework Comes Under ScrutinyThe pharmaceutical industry wants to speed up the variations process by

eliminating redundant assessment by different national agencies in the European Union.

Sean Milmo

is a freelance writer based in Essex,

UK, [email protected].


Pharmaceutical Technology Europe JUNE 2015 13

Additional workload, more delays, and higher costs

On the contrary, pharmaceutical companies complain that the

grouping and worksharing arrangements can lead to more

delays than previously in the processing of variations, while at

the same time pushing up costs. ÒIn practice, the system does

not appear to have been drastically simplified,Ó says

Stepniewska. She cited, as an example, the need for details of

individual variations within a grouping, whereas previously,

combinations of multiple minor changes could be filed as a

type II variation. ÒThere is no reduction in the administrative

workload,Ó she continues. ÒSome companies also report an

additional workload associated with the need for a regulatory

authorityÕs confirmation that a proposed grouping is acceptable.Ó

National agencies are sometimes not accepting variations

in groupings because they would take too long to assess due

to their number and complexity, according to the European

Federation of Pharmaceutical Industries and Associations

(EFPIA). The association estimates that with worksharing,

the CMDh (the co-ordination group running the DCP mutual

recognition procedure) can take as long as four weeks to

allocate the assessment task to an individual member state.

ÒThis adds a significant delay to variation processing timelines,

which does not encourage the use of the work-sharing scheme

by marketing authorization holders,Ó says an EFPIA spokesman.

In a guideline on worksharing (5), the CMDh outlines

processes that could take as long as 150 days with the

inclusion of a Òclock-offÓ period to allow for the supply of

supplementary information by the marketing authorization

holder and its assessment. National agencies are generally

having difficulties meeting the time limits on the completion

of assessments as stipulated in the EUÕs variations legislation.

ÒLess than one out of five variation procedures for type

IB and II currently starts on time,Ó says Stepniewska.

Speeding up variations assessments

EGA and other pharmaceutical industry associations want to

speed up the way variations to APIs are handled by eliminating

the need for similar API variations to be evaluated separately by

different agencies. ÒOur member companies report that they

are dedicating a growing part of their marketing authorization

maintenance activity to API-related changes,Ó Stepniewska

explains. ÒIt is certainly not desirable to continue having

multiple non-synchronized, uncoordinated procedures where,

in effect, the regulatory information to be assessed is identical.Ó

The solution could be for API producers to be given the

responsibility of dealing with the regulatory aspects of

changes to their products. Ò[There could be] a certification-

based procedure for all APIs to facilitate and speed

up the submission and maintenance of API regulatory

information through a direct relationship between regulatory

authorities and API manufacturers,Ó Stepniewska says.

Another concern is the amount of information from GMP

certificates being required by some agencies for variations

assessments. ÒThere should be a way to exclude routine GMP-

compliance activities from the variation process,Ó says the

EFPIA spokesperson. ÒOne suggestion is to have a centralized

database in the EU for all licence holders to give the complete

GMP status of API suppliers so that this [information] could

be accessible to all EU national authorities and the EMA.Ó

Despite the introduction of the new variations system, their

assessment is still being dogged by different approaches by

national agencies. ÒThere have been improvements since

the implementation of the amended regulation,Ó says the

EFPIA spokesperson. ÒBut there are still some differences

in approvals for type IB and II categories across national

authorities.Ó There are even differences between agencies

in the classification of variations indicating that there is

still work to be done in even removing basic regulatory

inconsistencies in the EUÕs variations procedure.

References1. EU Regulation, Amendments to Regulation 1234/2008 on the

examination of variations (Brussels, August 2012).2. A. Ganan and I. Gravanis, “Procedure Management of

Variations,” presentation at EMA meeting: Industry Stakeholder Platform on the Operation of the Centralized Procedure (London, 24 April 2015).

3. EU Regulation 1234/2008, Examination of variations to the terms of marketing authorizations (Brussels, November 2008).

4. EU Directive 2010/84/EU, Pharmacovigilance directive on medicinal products for human use (Brussels, December 2010).

5. CMDh, Best Practice Guide on Worksharing, CMDh/297/2013/Rev, February 2015 (London, February 2015). PTE

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Process analytical technology (PAT) has revolutionized

pharmaceutical manufacturing by enabling the

design and development of well-understood processes

that consistently deliver quality products. The ultimate

goal, under the quality-by-design (QbD) initiative, is to

build quality into the product rather than traditional

batch testing at the end of the manufacturing process.

Emil Ciurczak from Doramaxx Consulting; Tim Freeman,

managing director of Freeman Technology; and

Alon Vaisman, product development manager,

process systems at Malvern Instruments, spoke to

Pharmaceutical Technology europe about the benefits

of PAT in solid-dosage manufacturing as well as the

strategies for PAT implementation.

Key driversPTE: What are the key drivers for the

adoption of PAT in pharmaceutical

manufacturing and why is uptake slow

within the industry?

Ciurczak (Doramaxx Consulting): The key drivers

are and will be the economics of the industry. There

is pressure from countries to reduce costs on both

generics and proprietaries. New drug introductions

in Germany, for example, are allowed to cost more

than existing products only if a significant benefit is

demonstrated.

The United States Congress is bending to pressures

from the largest lobby in the US: AARP. They are

demanding lower drug prices and, with our new

Republican-controlled Congress, cost-cutting will be

the order of the day. PAT, well-executed, is the best

way to immediately lower cost of goods sold.

Freeman (Freeman Technology): PAT is a

fundamentally important aspect of any modern

pharmaceutical processing environment where

the need for quality and efficient manufacturing is

paramount. As the industry develops new products

and processes, it is essential to scrutinize the

characteristics of the in-process materials throughout

the manufacturing cycle to ensure that quality is

met and patient safety is guaranteed. This analysis

requires suitable tools applied at each step of the

manufacturing process. Significant progress has been

made in the past 10 years since the introduction of

the PAT initiative, but many processes remain poorly

understood and un-optimized.

Unlike many other powder processing industries, the

pharmaceutical sector is challenged by the need for

rigorous validation of its processes and measurement

techniques, which introduces additional hurdles to the

adoption of in-process monitoring and control. This

challenge is further exacerbated when implementing

real-time release testing, where measurements are

Adeline Siew, PhD

Unlocking the Vast Potentialof PAT in Solid-Dosage

ManufacturingPAT holds the key to real-time quality assurance and

consistent product quality in pharmaceutical manufacturing.

14 Pharmaceutical Technology Europe JuNe 2015 PharmTech.com



taken in real time and a decision

about product quality is almost

instantaneous.

Vaisman (Malvern Instruments):

One of the key drivers for the

adoption of PAT is the growing

demand for higher drug quality

and efficacy, both from regulators

and the public. Within the industry,

there is increasing recognition that

these demands cannot be met by

the traditional approach of relying

on final quality-control testing, but

rather that a detailed understanding

of all aspects of the product and

of the associated manufacturing

process is required. PAT can provide

the information needed to exert and

maintain effective process control,

and consequently, the necessary

assurance of quality and efficacy.

A second driver is the need to bring

products through to market more

quickly. Time to commercialization

has a major and direct impact on

the bottom line, both for generic

manufacturers (being first to file)

and innovators (time to manufacture

under patent). More efficient

commercialization calls for the

use of enabling tools that produce

data faster than can be achieved

by applying traditional technologies

in an analytical laboratory. Using

appropriate PAT makes it quicker to

implement the design of experiment

(DoE) approach associated with

QbD, and to fully scope the impact of

critical process parameters (CPPs).

Several factors are responsible for

the relatively slow uptake of PAT in

the pharmaceutical industry despite

these powerful drivers. Firstly, there

are perceived regulatory hurdles,

although it would seem that there is

little evidence to support this view.

Indeed, FDA is actively encouraging

and promoting the use of PAT to

demonstrate rigorous understanding

and control of the manufacturing

process and the parameters

impacting product quality. In some

instances, there is also a concern that

the use of PAT will reveal previously

unknown quality issues which will

then need to be addressed—the

potential downside of developing a

greater understanding of process and

product performance.

Finally, I would suggest that the

scarcity of widely accepted standards

for equipment and process design

is also an issue, especially against a

backdrop of historically low levels of

equipment utilization. Almost every

PAT implementation is essentially

unique, or considered to be so by

the end users who also have no

clear guidance as to what analytical

methods need to be applied in each

case. Furthermore, PAT is typically

being used to push manufacturing

practice towards relatively unfamiliar

performance standards. As a

result, the introduction of PAT is

often associated with demands for

customization, increased validation

burdens, and substantial engineering

efforts on the part of instrument

manufacturers and the end users, all

of which are barriers to uptake.

Implementing PAT in pharmaceutical processes

PTE: What are the main

challenges and key

considerations when it

comes to implementing

PAT in pharmaceutical development

and manufacturing?


In many cases, the challenges of

implementing PAT are linked directly

with the reasons outlined for its

slow uptake. For example, the lack

of standards increases the workload

associated with producing a fully

fit-for-purpose solution for any given

application. Engineered solutions are

used to adapt available PAT tools to

evolving needs, but in the absence

of standards, the cost, time, and

most importantly, the risk associated

with each solution is higher than it

should be.

Key considerations to address

when it comes to using PAT include

the need to rigorously assess what

information is required and the ability

of a proposed PAT tool to deliver it

reliably. PAT brings value by enabling

faster experimentation, more efficient

scale-up, and/or by increasing

confidence in the quality and stability

of the manufacturing process, and

ultimately, the end product. However,

it will only deliver these benefits by

measuring relevant data in a timely

and robust way. Scalability is also an

important factor to be considered

within this context because ideally,

the same PAT tool will deliver all

of these benefits by transferring

with the product, from R&D

through scale-up into commercial

manufacture.

Finally, method development is

an important consideration when it

comes to PAT because it affects how

the information generated by the PAT

device will relate to results measured

using established quality control (QC)

techniques. Correlations between

QC and PAT data can be vital to the

acceptance of a PAT tool.

Freeman (Freeman Technology):

There are now many examples of

spectroscopic techniques being

successfully applied to blending,

granulation, and drying processes, as

well as measurements such as in-line

particle sizing and more traditional

measurements of properties

like temperature and moisture.

However, a significant outstanding

challenge, particularly within powder

processing, is the rationalization of

which material properties, for both

raw materials and intermediates, are

important in determining the quality

of the finished product.

Attaining this information is

the basis for improved product

development and formulation, but

also as a driver for the development

of new or better process analytical

technologies. Whilst there have been

a great deal of solutions through the

application of in-line spectroscopic

techniques and particle sizing

methods, there are other attributes

of particles, such as density, flow,

morphology and permeability, to

name a few, that are currently not

measured in-line and yet are broadly

recognized as being influential in the

critical quality attributes (CQAs) of the

final product, whether this is weight

variation or dissolution of a tablet, or

delivery performance of an API from a

dry powder inhaler.

Ciurczak (Doramaxx Consulting):

Quite simply, lack of experience in

a very conservative industry gives

managers pause before attempting

anything new and not already being

done. In other words, it is a lot

simpler to convince a director to

buy six new high-performance liquid

chromatography (HPLC) systems

Pharmaceutical Technology Europe JuNe 2015 15



than one new Raman or near infrared

(NIR) unit. Adding more people and

more equipment always worked in

the past, so why not keep doing the

same thing that made money before?

The instrument manufacturers need

to assure the producers of drugs that

they will ‘hold hands’ throughout the

early attempts at PAT and then follow

through by having knowledgeable

staff available.

PTE: What are the

strategies for successful

implementation of PAT

in pharmaceutical

development and manufacturing?


The implementation of a robust and

appropriate PAT toolkit should be

based on understanding the material

properties and process parameters

that are important in influencing

the quality of the finished product.

Some of these tools will be readily

available, such as NIR, and others

are still emerging or have yet to be

commercialized, such as the ability to

measure in-line particle morphology

or granule density following a batch

granulation process. A sensible

approach would, therefore, be one

whereby the identification of these

variables is first achieved and the

selection of available PATs is made.

Bear in mind though that there may

still be important material properties

that cannot be measured in real

time. Hence, the control strategy for

the process needs to account for

this absent information, either by

retrospective testing or by showing

through a QbD approach that such a

material property will not vary outside

of the acceptable criteria (defined

perhaps by off-line measurements) as

long as certain process parameters

are controlled within a specific

predefined range.


Regulatory documents relating to

PAT and QbD, which is covered in

detail in the International Conference

on Harmonization (ICH) guidance,

provide a framework for the

successful implementation of PAT.

The application of QbD involves

the systematic identification of all

CQAs and CPPs using a risk-based

approach, thereby highlighting those

variables that can be productively

measured using PAT. The next step

is to determine where in the process

stream the measurement should

be made to provide most value.

Potential PAT solutions can then be

usefully evaluated by considering the

following questions:

• How suitable is the analytical

method? Does the PAT measure

the parameter that you need it to?

• Can you trust and validate the

results that are generated? Does

the method robustly report data

that are representative of the

process stream and allow you to

securely differentiate between

poor and acceptable process

performance?

• What calibration procedures are

required to ensure data quality?

How easy is it to store and use the

generated data?

• Is the technology suitable for

its working environment? Are

the materials of construction

compatible with the process

stream and are requirements for

cleanliness/avoidance of product

contamination met?

• Does the proposed solution

address user requirements? How

easy is the hardware and software

to use? What routine maintenance

is needed?

• Are any requirements for versatility

met? Can the technology be used

for more than one product if

necessary?

Alongside this technical

assessment, it is also essential to

conduct a business-value review to

determine the economic value that an

investment in PAT will deliver to offset

its cost. An important part of this

review includes rigorous assessment

of the cost of implementation—the

investment associated with the

equipment and any associated

installation, qualification, and

validation work.

Applying PAT in solid-dosage manufacturing

PTE: PAT has been used

across many types of

operations in solid-dosage

manufacturing. Can you

provide some examples of how PAT

has been applied?


In raw materials testing (i.e., every

container of every lot), for example,

there have been a number of cases

where improper particle sizes were

delivered. In one specific case,

the micronized drug was delivered

instead of 100-mesh, granular

material; and it would have been a

disaster if used for a suppository

batch had the problem not been

detected by NIR. The United States

Pharmacopeia (USP) testing had

already approved the lot—sieving

only required that there be ‘no less

than 1% on a 100 mesh screen.’ There

wasn’t an allowance for smaller sizes

being sent.

In another example, a granulating/

drying process was run to ‘less than

1% moisture’ by Karl Fisher titration.

It was discovered that the drug could

exist as either a monohydrate or

hemihydrate after drying. Both forms

were physiologically equivalent, but

the hemihydrate had a six-month-

shorter stability profile, leading to an

earlier recall. This situation is easily

controlled by using NIR to control the

airflow and temperature.

Extending to clinical studies, errors

in packaging (leading to erroneous

correlation) can easily be avoided

by scanning 100% of the blister

packs with NIR or Raman to assure

compliance with the protocol non-

destructively. Also, HPLC results may

take days, while spectroscopic results

are immediate.


Examples of PAT from Malvern

Instruments that has been used to

improve solid- dosage manufacturing

include: the Parsum in-line particle

sizing probe for the optimization and

scale-up of granulation processes

and the Insitec online laser-diffraction

particle-size analyzer that finds

application in milling and spray-

drying control.

High-shear wet granulation is used

routinely to improve the properties

of tablet blends ahead of tabletting.

Such processes, however, are

notoriously difficult to optimize and

scale-up because of their sensitivity

to small changes in the formulation

or in the mixing regime. A QbD

approach can be used to develop

the knowledge required to minimize



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and control the risk associated with

moving such processes through to

commercial manufacture, and real-

time PAT is used to facilitate this

process. One of the tools deployed by

several global pharma companies is

a Parsum in-line particle-sizing probe

that measures the size of the growing

granules in situ within the granulator.

Using real-time particle-sizing

data, scientists can confirm that a

granulation is proceeding identically

at different scales to deliver granules

with well-controlled properties.

Experimental studies have shown

that batches of granules identified

as being comparable, on the basis of

particle-size data, go on to produce

tablets of comparable quality. Real-

time particle sizing is thus helping

to speed up process development

and to enable successful scale-up,

while at the same time reducing the

number of trial runs needed, thereby

saving highly valuable API.

Spiral jet mills are used extensively

in the pharmaceutical industry, for

example, to control the particle size

of active ingredients. Although these

mills are seemingly simple in design

and easy to operate, micronizing a

batch to the right (and often very

tight) specification can be challenging

due to gradual changes in the

performance of the mill and variability

of the feed material. Common

process optimization by iterative

sampling of small sub-batches to find

the right parameters and then ‘blind’

processing of the main batch results

in a higher risk of failing final QC and

of wasting valuable API.

Using an Insitec laser diffraction

analyzer to measure the particle

size of the material leaving a jet

mill, in real-time, makes it possible

to quickly assess the impact of

milling parameters such as material

feed rate and injector pressure.

This information can be used to

fully scope a milling process or to

identify conditions that will produce

a specified particle-size distribution.

The continuous analysis of mill output

enables a timely response to any

deviation from the set specifications

during the run. As a result, this

PAT can save time and money, by

reducing the length of trials and

the material required to identify an

optimal processing setup, as well as

by lowering the overall risk of out-of-

specification production.


The enthusiasm for, and the recent

adoption of, continuous manufacturing

within the pharmaceutical industry

has necessitated the successful

implementation of a number of PATs

across a range of process steps

incorporated within the continuous

manufacturing of tablets.

Work published by Vertex

Pharmaceuticals (1) in recent years

shows the use of a GEA Pharma

Systems ConsiGma continuous

manufacturing suite incorporating

spectroscopic characterization

methods for measuring water content

of product in a dryer and blend

uniformity of an intermediate prior

to compression. It also features an

in-line particle sizing technology

in the form of a Malvern Insitec for

measurement of particles following

the milling process.

Both techniques applied in this

appropriate manner provide real-

time assessment and the ability to

feedback relevant information to

permit control of the process should

changes need to be made to ensure

the product attributes remain within

the target specification.

Recent advances in PATPTE: What recent

advances in PAT tools have

you seen over the past five

years? Or what would you

identify as significant advances in PAT

for pharmaceutical solid-dosage

manufacturing?


I would say without hesitation that

continuous manufacturing is the

biggest boon to PAT/QbD in the past

20 years. A number of companies

are going full bore into this mode

of production. Several immediate

benefits have been seen:

• The footprint of a continuous

production facility is far smaller

than a traditional plant set-up,

which means lower land costs,

lower heating, ventilation, and air

conditioning (HVAC) costs, lower

warehouse costs (intermediates

need not be stored), and less

cleaning costs and time.

• There is no scale-up. The

experimental batches are the

production batch size. This fact

alone could add 12–18 months to

the patent lifetime.

• Design of experiments, geared

to give the design space for QbD

and run in a conventional manner,

would cost up to 20 times as much

as continuous manufacturing and

take weeks, whereas in continuous

manufacturing this DoE takes days.

This approach saves API, cleaning

time, allows more experiments,

and is run at the level that the final

batches will be produced.

• Finally, with constant monitoring,

any out-of-specification (OOS)

excursion can be immediately

spotted and production halted.

The amount of product lost is

minimized and costs contained.


There are a number of emerging

technologies within the PAT toolkit

that include numerical modelling

tools as well as techniques for

measuring attributes of the

in-process material, such as ribbon

density of a product leaving a roll

compactor. Certain attributes are

amenable to in-line measurements,

yet others remain challenging to

quantify within the process, such as

particle morphology and powder flow

properties. Nevertheless,

both are important powder

attributes that have the potential

to influence the characteristics of

the finished product.

For example, a blend may be

defined as having acceptable content

uniformity as it exits a continuous

blender, as measured by an NIR

probe, and it may have a suitable

particle size distribution following a

milling process. However, neither of

these measurements ensures that

the powder has the same particle-

shape characteristics as a previous

functional ‘batch,’ nor that it has

suitable flow properties. Given that

both morphology and flow can lead

to capping, weight variation, and

hardness problems, the absence

of this information explains why

variation in product CQAs is still

observed, even for processes

employing a number of PATs. In this

circumstance, the ability to predict



and to control all of the CQAs has not

been achieved.

Whilst there have been many

advances in PAT, there are still

a significant number of material

attributes that need to be understood

in regard to their influence on

CQAs. Once these relationships are

established, the next challenge is

to develop on-line measurement

techniques that permit the

measurement of these additional

properties to further interrogate

and control the complex processes

employed.


Over the past five years, there

has been an increasing push for

‘information rich,’ multi-parametric

analysis, especially in batch unit

operations prone to variability, such

as blending and granulation. The term

PAT is often synonymous with on- or

in-line measurement, because of the

value of such instrumentation for

process monitoring and control. PAT,

however, is actually defined more

broadly as ‘a mechanism to design,

analyze, and control manufacturing

processes…’ (2). So, for example,

we are finding that there is appetite

to use our Morphologi G3-ID, a

laboratory-based instrument, as a

PAT, because of the relevant data

and insight it is able to provide. The

Morphologi G3-ID enables particle

size and shape measurement and

chemical identification, by combining

automated imaging with Raman

spectroscopy. It can, therefore, be

used to assess, for example, the

homogeneity with which an active

is distributed within a blend or to

assess changes in the size and

shape of an active caused by specific

processing steps.

A second trend is the drive towards

continuous manufacture now

that the successful, cost-effective

implementation of this approach has

been amply demonstrated. Because

continuous manufacture calls for

analyzers to work together and for

automated process control, it has

helped to stimulate the development

of new software solutions that

simplify analyzer integration, such

as Malvern Link II. In addition, new

instrumentation such as the Parsum

IPP80 probe has been developed for

easy data transfer and use to enable

the more complex control strategies

required for continuous manufacture.

References1. P. Hunter et al., AAPS News Magazine,

16 (8) 14–19 (2013).

2. FDA, Guidance for Industry

PAT—A Framework for Innovative

Pharmaceutical Development,

Manufacturing, and Quality Assurance

(Rockville, MD, September 2004). PTE


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Pharmaceutical Technology Europe JuNe 2015 19


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New cell-culture techniques, biomanufacturing formats, biological

products, and the expansion of single-use applications are driving

rapid change in the biopharmaceutical market. Pharmaceutical

Technology europe spoke to industry experts in the field of

bioprocessing to identify the key trends impacting the industry in 2015

and beyond.

Novel expression systems and cellular platformsAlternative platforms for industrial development may prove to be

more cost-effective than prevailing cell models. While Chinese

hamster ovary (CHO) cells are commonly used for the production of

recombinant protein therapeutics, alternative expression systems are

gaining popularity, according to William Whitford, senior manager, cell

culture, at GE Healthcare Life Sciences. “Avian lines (e.g., duck embryo

quail sarcoma and chick embryo fibroblasts) have been reported to

transfect well, have promoters that work with mammalian genes, and

grow (i.e., culture expand) faster. [These lines also] promise higher

levels of cell density and specific expression, reduced generation of

ammonium and lactate, and reduced product cell-surface fucose,

resulting in enhanced antibody-dependent cell-mediated cytotoxicity

(ADCC) activity,” Whitford told Pharmaceutical Technology europe.

EB66 is an example of such an avian origin line; these cells were

shown to reach high cell densities at short population doubling times,

Randi Hernandez

and are believed to offer enhanced

biological activity as a result of their

natural ability to produce

glycoproteins with low fucose, a

feature that is correlated with

improved receptor binding (1).

Baculoviral insect cell systems have

also been gaining popularity as a

substitute for commonly used

production schemes for recombinant

protein production and have been

effective vectors for large-scale

production of human monoclonal

antibodies (mAbs) (2).

New formats Transient transfection. Instead of

introducing a DNA into a cell’s host

genome, genetic information can also

be introduced into a cell (though not

integrated into the cell’s genome) via

pores in a cell membrane—a process

known as transient transfection.

Recent advances in cell culture and

transient transfection have allowed

cell lines to be transiently transfected

to produce large amounts of

recombinant proteins before the

genetic material is degraded and/or

diluted. Whitford says that transient

transformation is easier and cheaper

than the “standard engineering of

stable transformants.” Using

retroviruses to genetically modify T

cells can also be a concern because of

“their propensity to integrate near

start sites of genes, which could lead

to gene dysregulation, cell

transformation, and oncogenesis” (3).

The use of nonviral transposon

systems or direct RNA electroporation

could, therefore, be effective

alternative transduction options for T

cells and in other applications as well.

According to Life Technologies, the

benefits of transient transfection

include creating large quantities of

post-translationally modified and

active mammalian protein in 3–7

days, the ability to express proteins in

mammalian cell culture facilities with

shake flasks and a platform shaker,

and the easy purification of secreted

proteins from serum-free cell-culture

media (4). Transient expression also

eliminates the cell-expansion step

required for standard approaches,

thereby helping to reduce

manufacturing time and potentially,

manufacturing costs.

Top Trends in Biopharmaceutical Manufacturing: 2015Pharmaceutical Technology Europe spoke to experts in the

field of biopharmaceutical manufacturing to gain insights

on top trends that are currently shaping the industry.



Biopharmaceutical Manufacturing

Continuous biomanufacturing.

Increasing titres as a result of

advances in process efficiencies

means that there is more pressure on

downstream processing. Though

continuous processes such as

perfusion are widely adopted

upstream, downstream continuous

methods are slowly but surely

catching up to upstream processes.

Chromatography techniques are

gradually becoming continuous. “For

example, a series of small columns

have been demonstrated to mimic

one single large column with a

diameter and a bed height equal to

the total bed height of the smaller

columns,” explains Whitford.

“Multicolumn setups have been

characterized in bind-and-elute (B/E)

mAb capture steps. There are even

valve-and-column arrangements that

lengthen the stationary phase to

allow high-solute loadings to the

process,” he adds. “From a features

and benefits point of view, quasi-,

pseudo-, or even partially-continuous

capture chromatography can provide

the benefits of a more continuous

[setup].”

Christel Fenge, vice-president of

marketing and product management

fermentation technology at Sartorius

Stedim Biotech, says that while a few

teams are working on establishing

end-to-end continuous processes,

she predicts it will take the industry

at least a decade or more before it

achieves robust commercial

continuous processes that are

completely sequential and closed in

an end-to-end loop. “Managing

process deviations in a GMP context

is not trivial and the old topic of

batch definition needs to be

revisited,” Fenge states. “There are

also still [performance] gaps with

regard to single-use sensor tools,

valves, and pumps.” Indeed, the

experts agree that industry pilot

evaluations of end-to-end processes

will have to continue to properly

weigh the advantages and

disadvantages. “Success at larger

scale and under GMP and

commercial manufacturing

environments will be the next hurdle

for end-to-end continuous

manufacturing,” Parrish Galliher,

chief technology officer, upstream,

at GE Healthcare Life Sciences

asserted. “We expect that the next

five years will reveal the ultimate

place and role of continuous

manufacturing.”

Progress in perfusion: New cell-culture techniquesHigh-density perfusion/intensified

perfusion. With manufacturers

constantly trying to reduce material

costs and produce more drug in a

shorter timeframe, they have looked

to new methods to achieve those

goals. Alternative culture methods are

growing in popularity, according to

Whitford. “Intensified perfusion is

growing in popularity for [the]

production of protein

biopharmaceuticals,” Whitford notes.

He says that various publications have

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described intensified perfusion in

applications such as cell banking,

seed expansion, and cell cultivation

for production. Perfusion with

intensification is a continuous

bioreactor process characterized by a

cell-recycle system. Intensification

allows titres to increase, with cell

mass concentrations reaching more

than 100 million cells/mL at laboratory

scale and mAb products reaching

concentrations of more than 20 g/L,

Galliher states.

Typically, intensified perfusion is

applied to mAb production, says

Fenge, as these molecules are

relatively stable. A key benefit of

intensified perfusion is the “space-

time yield,” says Fenge, as a 2000-L

single-use bioreactor can produce as

much antibody as a bioreactor that is

five to 10 times larger, and does so

with a smaller footprint. “Another

benefit is speed to market, as the

scale used for Phase III trials is the

same as commercial manufacture,”

meaning that “no further scale-up is

necessary.” Compared with fed-batch

operations, cost benefits of

intensified perfusion vary, says

Fenge. “Bottom line, the cost really

depends on the individual case,

framework, and constraints—but

there are clearly scenarios where

there is a tangible overall cost

benefit.” Galliher notes that a

disadvantage of intensified perfusion,

however, is that high cell mass

overloads conventional cell-removal

systems, bottlenecking downstream

purification operations.

Hollow-fibre perfusion,

packed-bed bioreactors, and

bioreactors with microcarriers. In

some types of perfusion, cells are

bound or grown on a membrane.

Other types of perfusion require

filtration or centrifugation to retain

cells floating around in the bioreactor.

Whitford notes that solid substrate

systems, used for attachment-

dependent cells, can in some cases

produce lower apoptosis rates and

produce fewer contaminating cell

metabolites (5). “In perfusion systems

with cells bound to a solid substrate,

cells grow more naturally and with

less traumatic mixing/agitation and

shear,” Whitford writes. Furthermore,

all perfusion systems can in some

applications provide “recombinant

proteins/antibodies that are purer,

more like native proteins, and more

consistent in their biological activities

than fed-batch bioreactors, such as

having fewer variations in

glycosylation” (5).

In particular, animal cells are

increasingly being seeded within

cartridges of hollow-fibre perfusion

bioreactors. Hollow fibres allow for

3D cell culture. The 3D fibres are

biomimetic of actual human tissue,

allowing cell interaction via numerous

contact points (6). Nutrients and

waste are exchanged through

capillaries, with fresh media diffusing

outside of the fibres into the cells in

the intercapillary space and spent

culture media flowing back into the

fibres for eventual removal. Hollow-

fibre perfusion has been shown to

create a more constant culture

environment in terms of nutrients and

metabolites, and products can be

harvested continuously at higher

concentrations than they can from

suspension cultures over longer

periods of time (5). This closed

platform can be applied to various cell

types, including vaccines, mAbs, stem

cells, and cell therapies (5).

Conversely, Fenge says she

believes that hollow-fibre bioreactors

are outdated, and are “only used for

making antibodies for diagnostic or

research purposes, if at all.”

Packed-bed bioreactors, on the other

hand, have gained traction in

emerging economies for the

production of vaccines, although

Fenge acknowledges it is difficult to

ensure homogeneity inside of a

packed bed. “Essentially, it is very

difficult or impossible to monitor pH,

dissolved oxygen or cell density in a

reliable way inside a packed bed.

Also, scalability is a challenge, as

these systems are difficult to scale in

a linear way and typically, users

scale-out, i.e., they use multiple

parallel bioreactors to produce the

amounts needed,” Fenge explicates.

“This [scale-out method], in turn,

increases the operational and

analytical costs compared with an

approach that can be scaled in

volume.”

Microcarriers are also an attractive

option for the production of vaccines,

as “they can be used in a classic

stirred-tank bioreactor in a

homogenous cell-culture mode.”

While Fenge recognizes that not all

vaccines can be produced in

suspension culture, she says that this

process is easiest because no

“complex seed expansion is

necessary, where cells need to be

detached from the carriers and

transferred to the next larger

bioreactor, no bead-to-bead

approaches [need to be] validated,

and no tedious preparation of the

carriers is required.” Galliher says that

while vaccines are being produced

more often with suspension cells in

conventional stirred-tank reactors, in

developing markets, “vaccines that

still require attachment-dependent

cells will expand in those new

territories.”

Cell therapies are expanding, and

many require attachment to a

surface, says Galliher. Microcarriers

and packed-bed bioreactors may be

most promising for the mass

production of stem cells in the

manufacture of regenerative

medicines, notes Fenge, but the

challenges that exist with vaccines

also exist with stem cells. Harvesting

the stem cells requires releasing

them from the attachment surface

using enzymes, which need to be

washed away in the final dosage

form, Galliher asserts. “Additionally,

the morphology of these cells may

have an impact on their

differentiation, leading to consistency

issues, or worse, [the production of]

nonfunctional cells,” adds Fenge. As

a result of these challenges, and

because there is an interest in

reducing the cost and complexity

associated with the processing of

attachment-dependent cells, there is

a big demand for suspension-adapted

stem cells. “We expect that

suspension-adapted stem cells will

become more widespread in the cell-

therapy space in the future,” Galliher

emphasizes.

Retrofitting for perfusion.

According to Whitford, existing

equipment and legacy systems are

increasingly being retrofitted to

enhance operational efficiencies.

While he says retrofitting for

single-use bioreactors is going on,


ES619406_PTE0615_022.pgs 05.23.2015 02:52 ADV black


retrofits of existing GMP processes

“tend to be substantially more

difficult.” Despite this fact, “the

selection of perfusion technologies

available for interface with stainless-

steel bioreactors is supporting retrofit

of an increasing number of

established stainless steel-based (and

hybrid) facilities.” Indeed, existing

research on the productivity of spin-

filter perfusion and alternating

tangential-flow perfusion

demonstrates that these perfusion

culture processes offer cost of goods

savings when compared with fed-

batch processes (7).

Although retrofitting existing

stainless-steel facilities for perfusion

is an option, Fenge thinks that this

procedure is “not at all

straightforward,” and it is much

easier to just “rip the old stainless-

steel upstream equipment out,

retrofit the cleanroom space with

new, single-use bioreactors, media

preparation, and storage solutions.”

She also says that increased

efficiencies can come from exploring

hybrid solutions with buffer mixing,

storage, and intermediate storage in

single-use bags.

The process mode of perfusion as a

whole needs improvement, says

Fenge, especially when it comes to

the creation of more robust cell-

retention devices, single-use pumps,

and sensor technologies. Fenge notes

there is also a clear gap in large-scale

single-use connectors, “as better cell-

culture results are achieved at large

scale if the recirculation loop is wide

enough to avoid high shear forces on

the cells.”

Single-use technologies Formal standards will drive

increased expansion of single use.

The focus on single-use is correlated

with an increased interest in modular

facilities, smaller bioreactors (from

10,000–20,000-L sizes to medium-

sized, 2000-L bioreactors), the need

for facilities to produce multiple

products in parallel, and the “need for

risk mitigation to better manage

strong attrition rates of products

coming through the pipeline,”

observes Miriam Monge, marketing

director, integrated solutions at

Sartorius Stedim Biotech. Single use

can now be seen in laboratory, pilot,

clinical, and commercial

manufacturing operations. Galliher

says that customer reports

demonstrate that after 10 years of

active use, single-use products were

shown to reduce capital cost by

40–50%, reduce operating costs by

20–30%, and reduced the time-to-

build by 30% when compared with

traditional stainless-steel technology.

“Over the past decade, the question

of whether single-use technologies

are feasible has dissipated, and they

have become an industry standard for

the manufacturing of clinical batches

in biopharmaceutical production,”

says Helene Pora, vice-president of

single-use technologies at Pall Life

Sciences. She adds, “Many

opportunities exist around bringing

more control through automation,

and the industry continues to focus

on robust and reproducible processes

with recording systems that create

more of a standard mode of

operation.”

Formal standards will drive increased expansion of single use.

Despite the process efficiencies of

single use, problems still exist,

namely, the assurance of product

quality, product integrity, vendor

supply-chain security, and the need

for “change control with timely

notification,” according to Monge. She

says that even more difficulties arise

when an end user attempts to audit a

single-use supplier, because there are

no true regulatory standards in place,

only guidelines.

There is now a trend, driven by end

users and suppliers, to facilitate the

adoption of enforceable standards for

single-use systems, Monge asserts.

“One of the greatest challenges that

end users currently face in their

selection and qualification of

single-use technologies is the fact

that very rarely are the vendors

working with the same testing

methodologies, whether we are

talking about the way in which they

determine and characterize

extractables from materials used in

single-use applications, characterize

leachables released from materials,

evaluate integrity testing methods, or

characterize particulate burden from

single-use systems,” she says. In

addition to the validation gaps

mentioned, the fact that tube sizes

remain small and that there are a

myriad of nonstandardized

incompatible sterile connectors on

the market also present problems,

adds Galliher. Single-use systems also

have a limited capacity in

downstream applications in general,

he concludes.

Monge points out that while the

The Bio-Process Systems Alliance

(BPSA) and BioPhorum Operations

Group (BPOG) have written

recommendations and guidance

documents on single-use systems,

and organizations such as the

American Society for Testing and

Materials (ASTM) and US

Pharmacopeial Convention (USP) are

gaining traction when it comes to the

regulatory control of extractables

and leachables, integrity testing, and

particulates, there will still be

performance gaps in the absence of

published standards by regulatory

bodies. “Standards will significantly

facilitate the adoption of single-use

systems, as end users will be able to

directly compare like with like, and if

these standards receive

endorsement from the regulatory

authorities, the end users will be able

to have a much higher level of

confidence when widely

implementing single-use systems into

commercial manufacturing,” Monge

stresses. The first approved

standards for single-use technologies

are expected in late 2015 or early

2016, she says.

Single-use for the conjugation of

ADCs. An antibody-drug conjugate

(ADC) combines the specificity of a

mAb with the efficacy of a cytotoxic

small-molecule compound. Christian

Manzke, director, marketing and

sales for integrated solutions at

Sartorius Stedim Biotech points out

that the original company that makes

a mAb can be a different company

than the one that performs the

conjugation of the product.

Furthermore, a separate company

altogether may perform the

formulation or filling duties

associated with said product. While




frozen mAbs or conjugates typically

travel to all of these different

processing locations in single-use

bags, says Manzke, it is not until

recently that single-use technologies

have been used for the conjugation

reaction itself. The biological,

aqueous, and large-molecule world of

ADC manufacturing is merging with

the chemical, solvent-based, small-

molecule pharma world, notes

Manzke. “Where single use is already

an accepted technology in the

biopharmaceutical industry, it was

not obvious that this [technology]

would become a success for the

solvent-based chemical linking

process as well. The fear about

noncompatibility of the plastics used

with the solvent-containing reaction

liquids or increased leachable profiles

led to a slow acceptance in the

market,” Manzke said. “Now we see

more and more companies weighing

the benefits over the challenges and

using single-use bags for the reaction

process and single-use crossflow

systems for the diafiltration and

concentration steps.” Because

single-use options offer a closed

system, they are ideal to use for

conjugation process steps. Closed

systems protect the operator,

environment, and the drug itself, and

ensure that residual cytotoxic

payloads or conjugate inside the

disposable assembly are contained,

Manzke adds. Single-use processing

equipment also facilitates equipment

sharing for multiple different ADCs.

New protein biologicals Allogeneic and autologous

therapies for adoptive immunity.

“Due to recent heightened investment

from large pharmaceutical companies

through acquisitions and partnerships

with academia and [subject matter

experts], the regenerative medicine

industry is gaining momentum, poised

to confer patient benefits for unmet

medical need and new profit areas to

prop up ailing conventional drug

pipelines,” asserts Kim Bure, director,

regenerative medicine at Sartorius

Stedim Biotech. Although initially, off-

the-shelf allogeneic therapies, such

as those exploiting mesenchymal

stem cells, were thought to serve a

universal population, Bure says that

the clinical success of these types of

therapies has been limited, and many

of the allogeneic products in

development have failed in late-stage

Phase III trials. As a result, many

researchers have turned to

autologous immunotherapies,

specifically in the form of chimeric

antigen receptor T-cell therapies

(CART or CAR-T). In these therapies

(which can be allogeneic or

autologous), T cells are harvested

from patients and genetically

engineered to recognize cancer

antigens.

The burgeoning interest in genetically engineered T cells has the potential to further drive the adoption of single-use systems and novel production paradigms.

So far, CAR-T products have been

shown to be dramatically effective

for blood cancers, but the therapies

still face challenges when it comes to

eliminating solid tumors. In fact,

some companies, such as MaxCyte,

in collaboration with the Johns

Hopkins Kimmel Cancer Centre, are

now doing research on the

introduction of the CAR construct as

a transiently expressing messenger

RNA (mRNA) for the treatment of

solid tumors. This approach is being

investigated as a method to control

the “on-target, off-tumor toxicity” of

most of the CAR-T therapies being

developed for blood cancer

indications (8). Other developers are

investigating a CAR-T “safety switch”

to address severe toxicity concerns

within the body due to cytokine

storm.

The burgeoning interest in

genetically engineered T cells has the

potential to further drive the adoption

of single-use systems and novel

production paradigms, says Bure,

given that the safety of the final

cellular product in these instances is

imperative. A mounting concern,

however, is that the cost of

autologous therapies will prove

unsustainable. “Unique, small-scale

lots that still require full-scale quality

control and release testing increase

the cost of goods and have the

potential to make these therapies not

commercially viable, so efforts to

create a historical design space

informed by extensive process

analytical technology data could

allow for reductions in testing and

movement towards real-time release

testing,” Bure explains. “Additionally,

with the advent of the Falsified

Medicines Directive, these blood-

derived therapeutics will possibly be

deemed as APIs from the initial

production stages by regulators,

forcing unique identifier techniques to

be implemented, such as 2D-data

matrices with 21 Code of Federal

Regulations-compliant tracking

abilities.”

Cell-based vaccines. There is also

an interest among vaccine

manufacturers in producing vaccines

in humanized cell systems as

opposed to what Bure says are

“antiquated egg techniques.” Bure

notes that researchers are currently

investigating dendritic vaccines for

hard-to-treat cancers, such as

glioblastomas.

References1. S. Olivier et al., mAbs 2 (4) 405–415

(July–August 2010).

2. D. Palmberger et al., J. Biotechnol. 153

(3–4) 160–169 (2011).

3. M.H. Kershaw et al., Clin. Trans.

Immunol. 3 (e16) (2014), doi:10.1038/

cti.2014.7 published online 16 May

2014.

4. Life Technologies, “Transient

Transfection,” www.lifetechnologies.

com/us/en/home/references/gibco-

cell-culture-basics/transfection-basics/

transfection-methods/transient-trans-

fection.html, accessed 24 April 2015.

5. W.G. Whitford and J.J.S. Caldwell,

BioProcess Internat. 7 (10) 54–63

(2009).

6. S.B.M. Usuludin, X. Cao, and M. Lim,

Biotechnol. Bioeng. 109 (5) 1248-58

(2012).

7. J. Pollock, S.V. Ho, and S.S. Farid,

Biotechnol. Bioeng. 110 (1) 206-19

(2013).

8. MaxCyte, “MaxCyte and The Johns

Hopkins Kimmel Cancer Centre

Announce Strategic Immuno-Oncology

Collaboration to Advance CAR T-cell

Therapies,” Press Release, 21 April

2015. PTE



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The delivery of an orally inhaled API to the deep lung can be

performed using different drug-delivery platforms, such as

nebulizers, pressurized metered dose inhalers (pMDI), and dry powder

inhalers (DPI). DPIs are increasingly becoming a more important drug

delivery option and are expected to hit double-digit figures, reaching

global sales of $31.5 billion in 2018 (1).

DPIs are conventionally formulated using a carrier-based approach,

in which the API is size-reduced until it reaches an inhalable particle

size and is further blended with a lactose carrier to enable dose

metering and to improve powder flowability and dispersibility. Even

though this formulation approach is the most commonly used, it

presents several drawbacks. To overcome the limitations, as well as to

address the renewed interest in pulmonary delivery of biotherapeutics

and other advanced therapies, several alternative particle engineering

approaches have been devised over the years, such as the production

of composite particles by spray-drying where the API is embedded in

an excipient matrix.

Although the development of a DPI seems straightforward, it is

a complex area that integrates multiple fields of knowledge. In a

general way, the success of a DPI produced using a carrier-based

formulation approach will be determined by the API physicochemical

properties, the formulation composition and process, the device

and operating conditions, the patient–device relationship, the

environmental variables, and ultimately, patient compliance. In

this article, Gonçalo Andrade, business development manager at

Hovione, spoke to Pharmaceutical Technology Europe about the

key considerations when developing an orally inhaled dry-powder

inhalation formulation.

A Q&A by

Adeline Siew, PhD

Developing an Orally Inhaled Dry Powder Formulation— A Complex Itinerary and a Technological ChallengeSuccessful drug delivery via a dry-powder inhaler is determined

by the API physicochemical properties, the formulation composition and process,

the device and operating conditions, the patient–device relationship,

the environmental variables, and ultimately, patient compliance.

PTE: What causes

agglomeration of drug

particles in DPI

formulations and how

does it affect drug delivery into the

lungs?

Andrade: Regarding the carrier-

based approach, it is generally

recognized that the API particles

should have an aerodynamic particle

size between 1 to 5 micron for optimal

deep-lung targeting. However, such

small particles are characterized by a

high surface energy; therefore, they

tend to be very cohesive and prone

to agglomeration, which can not only

lead to uniformity challenges upon

formulation with other excipients

but also result in poor flowability and

dispersibility of the drug dose during

aerosolization.

The agglomeration behaviour of the

drug particles is primarily dictated by

the API processing history. Primary

(e.g., crystallization) and secondary

(e.g., top-down technologies such as

jet milling) processing confer specific

attributes to the API particles, which

will ultimately determine the cohesion

(API–API) and adhesion (API–carrier)

forces of the API. It is, therefore,

clear that the particle engineering

technologies used to size-reduce

the API crystals will impact the

powder interfacial properties and

consequently, the powder fluidization

and aerosolization.

Although there are several particle

engineering technologies available,

jet milling (JET) is still the most

commonly used. In this case, the

particle comminution is based on

particle–particle and particle–wall

collisions due to the turbulent stream

created by the insertion of a grinding

gas. On the other side, through a wet

polishing (WET) approach, the API is

suspended in an anti-solvent system

and is size-reduced by particle–

particle and particle–wall collisions,

being then isolated by spray drying to

obtain a dry powder as the final

product. The presence of an anti-

solvent during the WET comminution

process reduces the high energy

input that occurs at the particle

surface during the JET micronization

process, preventing the creation of

local hot spots that could result in the

formation of undesirable product

26 Pharmaceutical Technology Europe JunE 2015 PharmTech.com


Formulation

properties such as amorphous domains

and/or changes in the API polymorphism,

especially on the particle surface.

In general, API particles size-reduced

by WET present a lower surface area,

rugosity, and water content; a higher bulk

density; and a quicker electrostatic charge

dissipation in comparison to powders

micronized by JET. Consequently, the

WET API particles have the tendency to

show higher adhesion to the carrier than

cohesion to themselves. Relative to JET

particles, however, WET materials show

lower adhesion to the carrier surface,

probably due to the smoother ‘polished’ API

surface with a smaller number of contact

points. These results show that different

processing histories can change the

powder interfacial properties, namely the

tendency to agglomerate and, according to

the formulation composition and strategy

used, can potentially impact API content

uniformity and the powder aerosolization

performance.

Another alternative to overcome the

constraints discussed previously is to

use engineered particles, created from a

solution; spray drying has been an enabling

technology for most of the platforms

described in the literature and/or is

commercially available. This technology can

produce inhalable particles with controlled

particle size, morphology, surface

properties, and density by manipulating

formulation composition, such as the

inclusion of surface-active agents and

process parameters. This increased control

over the powder properties allows the

optimization of the powder aerosolization

behaviour and dispersability, which

potentially allows for reduction of the

API dose while maintaining the amount

delivered to the target site. Examples

of these ‘special’ particles with several

patents protecting their production include

Pulmosol and PulmoSpheres technology

developed by Nektar Therapeutics,

Technosphere by MannKind Corporation,

AIR/ARCUS technology by Alkermes, and

iSperse from Pulmatrix and Hovione.

PTE: The strong cohesion forces

can be a challenge when handling

the powder during manufacture

or when metering and filling a

DPI. How do you approach this problem?

Andrade: The vast majority of DPI

products address the asthma and chronic

obstructive pulmonary disease (COPD)

market space. For these indications, API

dosages are typically in the microgram

range, requiring a bulking agent for

metering and handling the product. To

address these requirements, the size-

reduced APIs are usually blended with an

inert coarse carrier, lactose monohydrate

being the most commonly used in DPI

formulations. The main challenge of lactose

ordered mixtures is to balance the cohesion

(API–API) and adhesion (API–carrier) forces

that are necessary for ensuring a stable and

homogeneous blend while enabling good

aerosolization efficiencies.

In general, the API has to be adhesive

enough to attach to the carrier-surface and to

leave the capsule and the device, but not too

adhesive, so that the inhalable API is released

from the carrier surface upon oral inhalation.

Generally, the larger carrier particles impact

in the mouth and throat with a significant

amount of API still adhered to the surface,

while the remaining inhalable API will deposit

throughout the lungs; maximizing the latter

fraction is obviously the goal of the inhalation

drug-product formulator.

The cohesion forces can pose a

challenge during the blending step, causing

API agglomeration and consequently,

producing non-uniform powder blends.

A well-developed mixing procedure

is, therefore, crucial to ensure blend

uniformity and so that you can proceed

with product development.

Besides the cohesion and adhesion

forces, the electrostatic forces also play

an important role during the powder

handling, blending, capsule filling, and

even powder performance evaluation.

All of these manufacturing steps induce

electrostatic charging of the powder

blend. For this reason, approaches such

as the use of anti-static equipment, the

control of the environmental humidity,

and the establishment of relaxation times

to enable electrostatic charge dissipation

between each processing step are strongly

recommended.

PTE: How does the powder

mixing process influence

agglomerate behaviour of the

formulation in the DPI?

Andrade: For a successful blending

process, we need to provide an adequate

balance of energy to the formulation so

that the cohesion forces of the API are

overcome, enabling a homogeneous drug

distribution across the formulation.

By using carriers with different

properties in different mixing processes,

getting more value out ofmicronization

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[email protected]

catalent.com/micron

Pharmaceutical Technology Europe JunE 2015 27


Formulation

distinct powder blending, distinct

downstream processing, and

differential performances can be

observed. The results observed, when

different mixing processes are used,

support one of the two dispersion

theories—either the ‘filling’ of the

carrier active-sites hypothesis or the

drug/fines agglomerates-formation

hypothesis. Whether or not the

different addition order, mixing time,

and velocity, amongst other factors,

can impact the blend uniformity and

the final performance will depend on

the properties of the API and

excipients, as well as on the blending

procedure.

One of the challenges of the

scale-up of an inhalation product is

the transfer of the formulation

process from laboratory-scale,

where a low-shear mixer is

commonly used, to the large-scale

formulation, where both a high-shear

and a low-shear mixer can be used.

The different mixing principles can

affect the resulting blending

properties and consequently affect

the powder aerosolization behaviour

and thus affect downstream

processing and aerosolization

performance. In addition, the use of

a high-shear mixer can lead to

comminution of the lactose carrier,

increasing the percentage of fines,

which can consequently improve the

powder fine particle fraction (FPF)—

which is the amount of powder that

reaches the deep lung, presenting an

aerodynamic particle size

distribution below 5 micron—but can

hinder the bulk powder flow

properties. This can impact the

downstream processing as well as

change the aerosolization

performance previously developed

during laboratory-scale. On the other

hand, the use of a low-shear mixer

can lead to blend homogeneity and

content uniformity challenges, which

can also affect the downstream

processing and product development

strategy.

PTE: Can you elaborate on

the drug–carrier interaction

and its relationship with

aerodynamic performance

of a carrier-based formulation?

Andrade: The API and carrier

components and properties in

combination with the mixing process,

the environmental conditions, and

the device/flowrate requirements

will determine the aerodynamic

performance of the DPI. As previously

mentioned, there are two dispersion

theories, and according to the

carrier properties used and mixing

procedures, together with the API

cohesion and adhesion forces,

different scenarios can be observed.

In general, the increase of one

parameter does not always translate to

an advantage for the overall process.

A simple example is the incorporation

of lactose fines in the DPI formulations;

although it is known to increase the

powder performance by increasing the

FPF, it also affects the downstream

operations such as automated capsule-

filling rejection rate and the emitted

mass consistency. This means that a

careful balance should be taken while

developing a DPI product, because

a composition that favors the FPF

can have a deleterious effect on the

overall process. Therefore, it becomes

important to evaluate trade-offs and, in

this way, identify compositions that are

able to benefit the process as a whole.

Regarding some of the downstream

processes, such as the capsule filling

performance, we have observed that a

higher fill weight of the capsule benefits

the process by reducing the rejection

rate. Additionally, the amount of fine

particles and their particle size are also

major contributors to the rejection rate

in the manufacturing/filling process.

Lastly, to ensure a robust formulation

and guarantee a consistent drug

delivery and performance, we need

to minimize the process and materials

variability, by minimizing the intrinsic

batch-to-batch variability from both the

API and carrier properties.

PTE: How does carrier

particle size affect

inhalation performance of

the powder mixtures?

Andrade: Carrier-based DPI

formulation strategies typically

consider carrier systems composed

of coarse and fine grades of lactose.

To improve the FPF, the percentage

of fine lactose particles is increased;

however, this may also impact

negatively on the downstream

processing.

Some studies show a strong

relationship between the influence

of the lactose particle size and the

final aerodynamic performance.

In some cases, where the drug/

carrier agglomeration hypothesis

seems to be predominant, the fine

lactose particle size seems to be

the main contributor for the final

powder outcome. These fine lactose

particle attributes confer different

dispersibility and flow properties,

which can enhance or hamper the

downstream processes and ultimately

the final powder performance.

As a final remark, it is important

to point out that each inhalation

product has different properties. The

formulation and blending process

must, therefore, be assessed case

by case. That is why a holistic and

integrated approach must be taken

when evaluating different inhalation

drug-product development strategies

and carefully integrating the

formulation development strategy

with the delivery device. Hovione

has developed two DPI devices, the

two-cavity single-use DPI, TwinCaps,

and the capsule-based DPI, XCaps.

With our knowledge in both particle

engineering, formulation, and their

integration with the delivery device,

we were able to assist Daiichi-

Sankyo in developing the TwinCaps

Inavir inhaled product, currently the

category market leader in Japan for

the treatment of influenza.

Reference1. BCC Research, Pulmonary Drug

Delivery Systems: Technologies and

Global Markets, www.reportlinker.

com/p0715870/Pulmonary-Drug-

Delivery-Systems-Technologies-and-

Global-Markets.html, accessed 22 Apr.

2015. PTE

One of the challenges of the scale-up of an inhalation product is the transfer of the formulation process from laboratory-scale, where a low-shear mixer is commonly used, to the large-scale formulation, where both a high-shear and a low-shear mixer can be used.



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When designing a facility for pharmaceutical manufacturing, a

foremost consideration is preventing product contamination.

International GMP standards talk about contamination in terms

of contamination of the product itself and cross contamination

between different products and batches. In production areas,

especially where the product is exposed, the environment

needs to be tightly controlled and clean. A significant aspect

of this cleanliness is control of particulate by way of room air

filtration. This technology is well known and codified in several

widely used standards, primarily International Organization for

Standardization (ISO) 14644-1 (1) and, for the manufacturing of

sterile pharmaceuticals, Eudralex, Volume 4, Annex 1 (2). Other

factors besides air classification impact the potential for product

contamination and production area cleanliness, and these are

embodied within the concept of clean zones, which is defined

in general terms by the International Society for Pharmaceutical

Engineering (3) and ISO (4). The following factors must be considered

when establishing a strategy for levels of cleanliness in a facility.

Controlling contaminantsAir classification standards. The most obvious concern when

establishing zones of cleanliness is control of airborne particles.

Within a space, particle sources that represent potential

contamination include the process itself (materials and equipment),

the people, the garments being worn, and the pace at which activities

are undertaken. Particle control is obtained through filtration and

air changes. Filtration (typically using high-efficiency particulate

arrestance [HEPA] filters) ensures that clean air is entering the room.

Besides providing the room with a constant supply of filtered air, the

clean air can also be directed over specific operations within the

space. Air changes eliminate particles by exhausting contaminated air

and allowing clean, filtered air to fill in behind it.

Pressurization. Pressurization is a method of dealing with the

transfer of contaminates to adjacent spaces. It can be understood

as the direction that air flows between spaces. Positive room

pressure ensures an outward flow of air away from and protecting

a critical production area. Negative pressure provides airflow

into production rooms. If the intent is containment, then negative

pressure is preferred. Negative pressure is most often used when

dust is present in the operation or in multi-product oral solid-dosage

facilities where containment keeps product residue from leaving one

Eric Bohn is partner at

Jacobs Wyper Architects,

1232 Chancellor St.,

Philadelphia, PA 19107,

tel: +1.215.985.0400,

www.jacobswyper.com.

Designing Clean ZonesClearly defined zones of cleanliness help prevent product contamination.

area and contaminating adjacent

areas. Positive pressure is typically

used to protect product, such as in

aseptic processing where it keeps

foreign material away from the

sensitive area. Sometimes, such as

with vaccine production, positive

pressure is necessary to protect

the crucial production area while,

relative to the larger environment

outside of production, the area must

simultaneously be negative. In this

way, the crucial process is protected

while containing the biologically active

agents and thereby protecting the

environment outside of production.

Gowning. Gowning has several

functions. First and foremost, it

is about protecting the product.

The human body is continually

generating particles through hair

loss, shedding of dead skin, exhalant,

and saliva. Of the potential sources

of contamination in cleanrooms,

people generate the most, and

greater activity increases the release

rate of these contaminates. Gowning

(i.e., the covering of exposed hair,

skin, and, in some cases, the nose

and mouth) contains contaminates

and protects the production area

from the operators. When working

in such areas, residue can collect on

the exposed surfaces of the gowning

materials. If personnel enter other

areas, the residue can be transferred,

thus causing cross contamination.

Gowning procedures can keep these

contaminates from passing between

adjacent spaces by requiring disposal

of used gowns and re-gowning before

entering another production area.

Unidirectional flow. Closely

related to gowning and the

prevention of cross contamination of

adjacent spaces is the application of

unidirectional flow of people, material,

equipment, and waste, which occurs

when progress through a plant

proceeds in a linear manner such

that there are segregated entry and

exit sequences through the critical

production areas. Unidirectional flow

ensures that these areas are entered

only once before leaving. A simple

illustration is found in personnel flow.

The entry is highly controlled and

occurs only through a locker room

or gowning sequence. Once entering

a crucial production area, personnel



Clean Zones

leave through a separate exit and de-gown. The gowning,

which has been exposed to contaminates, is discarded,

thus ensuring that surface residue cannot be transferred

to other spaces. To enter another production area, the

operator must re-gown appropriately for the next space.

In a unidirectional flow facility, this linear movement

is applied to the various categories of flow, including

material, equipment, and waste.

Transition spaces. Transition spaces are closely

related to and often confused with gowning rooms.

While they are frequently the same space, their purposes

are independent. Transition spaces are used to achieve

proper pressurization and to maintain the integrity of

zones of different classification. When these can also

be used as gowning rooms, a high degree of efficiency

is achieved. In a sequence with cascading pressure,

passing through two interlocked doors of a transition

space ensures that the production area maintains its

overall pressurization. In addition, transition spaces

can be positively pressured to create a pressure bubble

or negatively pressured to create a pressure sink.

Depending on the specific layout and needs of the

facility, these are tools that can help protect the crucial

production area ensuring appropriate containment.

Cleaning. To maintain the functionality of production

spaces, routine cleaning is a crucial activity. The type

of drug product, its exposure within the room, and the

cleaning processes dictate the appropriate procedures.

Cleaning activities can range from simple vacuuming and

wipe down to robust hose-down and even fumigation.

The agents used and the severity of the washing activity

control the choices of room and equipment materials

and finishes. To withstand these procedures, the

interaction with the finish materials must be evaluated

and appropriate selections made. Virtually all production

spaces generate at least a few tools and equipment

that require cleaning in dedicated washrooms. Where

to locate these dirty processes in relation to crucial

production and how to return the clean materials is a

significant consideration in maintaining the cleanliness

of a zone. Washrooms need to be integrated into the

establishment of the cleanliness zones.

Quality risk management. The final consideration

and perhaps the most important, because it informs

all the others, is quality risk management. Evaluating

the quality risks within each of the factors discussed

facilitates informed and evidence-based decisions. The

current standard recognized by the US Food and Drug

Administration and globally is International Conference

on Harmonization Q9 Quality Risk Management. The

methodology described in this standard makes possible the

disciplined identification of actual areas of risk as opposed

to assumed or perceived risks. It provides a high level of

assurance that potential risks are dealt with effectively.

While facilities were previously developed using a number

of rules of thumb and commonly held beliefs, today there is

a growing demand that this disciplined approach be used.

ConclusionThe prevention of product contamination is a primary

concern in the design and operation of pharmaceutical

manufacturing facilities. To support and protect the

multiple stages of manufacturing, it is necessary to

have clearly defined zones of cleanliness. Applying the

factors discussed in this article can create hygiene zones

that provide varying levels of product protection. The

establishment of each zone needs to be appropriate

for the processes, product exposure, and risk of

contamination that are present. Central to instituting

zones that meet these needs is the application of quality

risk analysis. In today’s regulatory environment, rules of

thumb are no longer adequate. By carefully evaluating

the needs and risks inherent in the process being

maintained, hygiene zones can be properly applied.

The result is a greater assurance of product quality

while simultaneously optimizing productivity and the

cost of goods.

References1. ISO, ISO 14644-1 Cleanrooms and associated controlled environ-

ments—Part 1: Classification of air cleanliness (Geneva, 1999).

2. EC, EudraLex Volume 4: Good manufacturing practice

Guidelines, “Annex 1, Manufacture of Sterile Medicinal

Products,” (Brussels, 2008).

3. ISPE, “Glossary of Pharmaceutical and Biotechnology

Terminology,” www.ispe.org/glossary.

4. ISO, ISO 14644-6 Cleanrooms and associated controlled environ-

ments–Part 6: Terms and Definitions (Geneva, 2007). PTE




PEER-REVIEWED

Using a Dual-Drug Resinate Complex for Taste MaskingBox-Behnken modelling was used to optimize a resinate complex, to mask the taste of levocetirizine dihydrochloride and montelukast sodium in orally disintegrating tablets.Jyoti Mundlia, Rakesh Kumar Marwaha, and Harish Dureja

The goal of this project was to use complexation to

develop a dual-drug resinate system, to mask the

bitter taste of levocetirizine dihydrochloride and

montelukast sodium. The maximum drug loading onto

the resin, polacrilin potassium, USP (Tulsion 339) was

found to be 1:3 drug-to-resin ratio. Box-Behnken design

methods were used to study the effect of processing

parameters such as swelling time (X1), stirring time (X

2)

and pH (X3), on cumulative percentage drug release.

The cumulative percent drug release was found to

be minimal at extreme pH values (X3) and at high values

of swelling time (X2) and low values of stirring time (X

1).

The maximum drug release was found at high values

of stirring time, even at low values of swelling time.

One-way analysis of variance (ANOVA) was applied to

the cumulative percentage drug release to study the

fitting and the significance of the model.

Differential scanning calorimetry (DSC) and Fourier

Transform Infrared (FTIR) analyses of the optimized

formulation (F3) confirmed the drug complex formation,

suggesting that this model can be used to optimize

dual drug release. Finally, the dual-drug resinate was

formulated into orally disintegrating tablets (ODT),

whose quality was found to be within pharmacopoeial

limits. Drug release rate studies of the tablets in

simulated gastric fluid and in phosphate buffer (pH 6.8)

showed better results than the marketed formulation.

Results suggest that dual-drug resinate can be a cost-

effective and efficient method for masking unpleasant

taste in dual drug formulations.

Organoleptic (i.e., sense-related) characteristics can have

a significant impact on how closely patients adhere to

any therapeutic regimen (1). Taste is one of the key factors

that determine patient compliance and the commercial

success of any oral pharmaceutical formulation. Thus, it is

important for any oral dosage form to have a pleasing taste.

When the formulation is bitter or tastes bad, taste-masking

technology is used to make it more palatable to patients.

This involves the development of a system that provides a

physical barrier between the active substance and the taste

buds, modifies the drug solubility, or alters human taste per-

ception in some way (2).

Unpleasant taste may be masked (3) by various methods,

including the use of flavours, sweeteners and amino acids,

polymer coatings, effervescent systems, granulation,

freeze-drying (4), adsorption on ion-exchange resin,

solid dispersion, or chemical modification, for example,

using insoluble prodrugs, multiple emulsions, or salt

formation. Other techniques involve the use of liposomes,

microencapsulation, complexation, and rheological

modification.

Ion-exchange resins offer an inexpensive and effective

way to mask unpleasant taste in pharmaceuticals (5).

These resins are cross-linked polymers available as high

molecular weight polyelectrolytes having extensive charged

functional sites. They are water-insoluble and exchange their

exchangeable ions with charge ions in the surrounding ionic

medium (6, 7). The ion-exchange resin binds a drug to form a

drug-resin complex, known as resinate.

Recently, an alternative form, a “dual-drug resinate”

was introduced, in which two drugs are loaded onto

the same resin, providing drug-release characteristics

similar to those of single-drug resinates (8). The authors

applied the dual-drug resinate approach, using ion-

exchange resin to develop a drug-resin complex (DRC) to

improve the palatability of a combination of levocetirizine

dihydrochloride and montelukast sodium. This combination

of drugs is often used to treat respiratory distress resulting

from allergies.

Jyoti Mundlia is a research scholar at PDM College of Pharmacy,

Bahadurgarh, India. Rakesh Kumar Marwaha is an assistant professor

and Harish Dureja, [email protected], is an associate professor,

both at Maharshi Dayanand University, Rohtak, India.

Submitted: 9 July 2014. Accepted: 17 Nov. 2014.

CITATION: When referring to this article, please cite it as J. Mundlia,

R.K. Marwaha, and H. Dureja, “Using a Dual-Drug Resinate Complex

for Taste Masking,” Pharmaceutical Technology 39 (6) 2015.



Taste Masking

The goal was to mask the taste and formulate orally

disintegrating tablets (ODTs), which are much easier for

patients to take than conventional tablets, particularly when

patients are children or elderly, or when they are bedridden,

nauseous, or psychotic. ODTs use superdisintegrants, which

allow tablets to disintegrate instantaneously after coming

into contact with the tongue (9).

Box-Behnken design methods were used to optimize

the dual-drug resinate complex to mask the taste of

levocetirizine dihydrochloride and montelukast sodium, and

to formulate the optimized complex into ODTs. Levocetirizine

dihydrochloride is an active H1-receptor antagonist. It is the R

enantiomer of cetirizine hydrochloride, a racemic compound

with antihistaminic properties. Montelukast sodium is a

selective and orally active leukotriene receptor antagonist

that inhibits the cysteinyl leukotriene CysLT1 receptor (10).

Materials and methods

Materials. Levocetirizine dihydrochloride and montelukast

sodium samples were provided by Arion Health Care, Ltd.

Samples of United States Pharmacopeia (USP)-grade polac-

rilin potassium resin (Tulsion 339) were provided by Thermax,

Ltd. Other chemicals used in this project were analytical

grade; high-performance liquid chromatography (HPLC)-

grade solvents were used for HPLC analysis and HPLC-grade

water was used throughout this study.

Methods. Pretreatment of ion - exchange res in .

Approximately 20 g of Tulsion 339 resin was consecutively

Table I: Multiple linear regression for percent drug-resin complex (DRC) of levocetirizine dihydrochloride and

montelukast sodium.

Batch Swelling time

(X1)

Stirring time

(X2)

pH

(X3)

% CDR

of levocetrizine

dihydrochloride

Y1

% CDR of

montelukast

sodium

Y2

F1 -1.00 -1.00 0.00 82.88 29.24

F2 1.00 -1.00 0.00 52.92 12.09

F3 -1.00 1.00 0.00 99.19 65.84

F4 1.00 1.00 0.00 85.09 43.95

F5 -1.00 0.00 -1.00 8.45 39.68

F6 1.00 0.00 -1.00 1.39 22.55

F7 -1.00 0.00 1.00 19.15 15.52

F8 1.00 0.00 1.00 16.06 23.1

F9 0.00 -1.00 -1.00 17.89 14.56

F10 0.00 1.00 -1.00 0.26 29.76

F11 0.00 -1.00 1.00 21.63 15.84

F12 0.00 1.00 1.00 2.61 46.74

F13 0.00 0.00 0.00 66.53 17.08

F14 0.00 0.00 0.00 68.324 45.67

F15 0.00 0.00 0.00 66.872 43.768

X coefficients

for levocetirizine

dihydrochloride

-6.78 1.48 3.93 67.24 -

X coefficients

for montelukast

sodium

-6.07 +14.32 -0.67 - 31.03

Table II: Ingredients for orally disintegrating tablets of

levocetirizine dihydrochloride and montelukast sodium.

Ingredients Quantity (mg)

Dual-drug resinate 60

Sodium starch glycolate 10

Crospovidone 10

Magnesium stearate 2

Microcrystalline sodium 33

Talc 5

Mannitol 30



Taste Masking

washed three times with 100 mL of deionized water, 100 mL of 95%

ethanol, 100 mL of 50% ethanol, and finally with 100 mL of deionized water.

Supernatant was removed consecutively by sedimentation and decantation.

The washed resin was dried overnight at 50 °C in a hot air oven and kept in a

closed vial.

Optimization of drug-to-resin ratio. For this purpose, different quantities of

activated resin were transferred to 20 mL of deionized water and allowed to

swell for 30 minutes. Levocetirizine dihydrochloride and montelukast sodium

were added separately to each beaker at different ratios of drug: resin (1:1, 1:2,

1:3, 1:4, 1:5, and 1:6) and stirred using a magnetic stirrer for three hours at room

temperature. The mixtures were filtered and residues were washed with 5 mL

of deionized water. The unbound drug in the filterate was estimated by HPLC,

using Agilent 1200 series on Reliasil ODS 250 × 4.6 mm, 5-µm column operated

at 250 °C using methanol:water (78:22) as the mobile phase; flow rate was

maintained at 1.0 mL/min, and detection was carried out at 240 nm.

Preparation of drug resin complex. The DRC was prepared by batch process,

keeping the quantity of drug constant, and using Box-Behnken design

methods, as will be described subsequently. The resin was allowed to swell

in 20 mL water under magnetic stirring for 15–60 min at room temperature.

Levocetirizine dihydrochloride and montelukast sodium were added to the

swollen slurry at the maximum drug-to-resin ratio, under magnetic stirring, and

the resultant mixtures were stirred for one to six hours. The pH of the solution

was adjusted to 1.2, 4.0, and 6.8. The DRC was separated by filtration, and

residue was washed with 5 mL of deionized water to remove any uncomplexed

drug, and dried at room temperature. The complex was then stored in an air-

tight glass vial.

Optimization of process parameters. Statistically designed experiments

using Box-Behnken methods (Design-Expert 8, Version 8.0.7.1 software) were

performed to study the effect of three factors—swelling time (X1), stirring time

(X2), and pH (X

3) on drug loading.

Box-Behnken design is an independent quadratic design in which the

treatment combinations are at the midpoints of edges of the process space

and at the centre. It is a rotatable (or near rotatable) design, and requires three

levels (low, medium, and high) of each factor. The study of three factors at

three levels (-1, 0, +1) using Box-Behnken design leads to 15 complexes of drug

and resin (F1–F15). These formulations (F1–F15) are listed in Table I.

Characterization of optimized DRC:

• Differential scanning calorimetry (DSC). The DRC was sealed in an aluminium

pan. The reference was an empty sealed aluminium pan. Nitrogen flow rate

was maintained at 60 mL/min, heating was done at a ramp rate of 10 °C/ min

with equilibration at 30 °C. The sample was heated until the tempereature

reached 350 °C.

• FTIR studies. FTIR analysis was performed using IR Affinity-1 FTIR, to identify

the drugs. A total of 2% (w/w) of DRC was mixed with dry potassium bromide

(KBr). This powder mixture was then dried and further compressed into KBr

discs under a hydraulic press at 10,000 psi. Each KBr disc was scanned over

a wave number region of 400–4000 cm-1. The characteristic peaks were

recorded.

• In-vitro dissolution rate study of DRC in 0.1 N HCl and phosphate buffer (pH

6.8). Drug-release studies were performed in a USP XXII Type II tablet disso-

lution apparatus (LabIndia DS-8000), using 0.1 N HCl (pH 1.2) and phosphate

buffer (pH 6.8), with 0.5% sodium lauryl sulphate as dissolution media. A DRC

equivalent to 5 mg of levocetirizine dihydrochloride and 10 mg of montelukast

sodium was taken in 900 mL of each dissolution media. The temperature and

speed of rotation were maintained at 37 ± 0.5 °C and 50 rpm, respectively.



Taste Masking

Samples (10 mL) were withdrawn at suitable time inter-

vals, filtered through a nylon filter, and analyzed, directly

or after appropriate dilution, for drug concentration using

HPLC at 240 nm. The cumulative percent drug release was

calculated.

• Sensory evaluation for bitterness of DRC. A bitterness

evaluation test was performed to compare the bitterness

of the DRC to that of each of the drugs individually. Six

healthy human volunteers evaluated the effectiveness of

taste masking. Each volunteer held a DRC equivalent to a

dose of 5 mg of levocetirizine dihydrochloride and 10 mg

of montelukast sodium in his or her mouth for 10 seconds,

then spat out the mixture and rinsed his or her mouth

with distilled water. Their perceived bitterness levels were

recorded instantly and then after 10–30 seconds, using

the following scoring values: 0 = tasteless, 1 = slight, 2 =

moderate, 3 = strong, 3+ = very strong (11).

Preparation of tablets. Using direct compression, mouth-

dissolving tablets of the DRC were made. The equivalent

amount of both drugs was taken. The tablets were prepared

using crospovidone and sodium starch glycolate as

superdisintegrants (see Table II). All the ingredients were

accurately weighed and passed through mesh #60. The

powder blend was evaluated for micromeritic properties such

as angle of repose, bulk density, tapped density, powder flow

properties, and porosity. A mixed blend of DRC and excipients

was then compressed to form tablets, each weighing 150 mg.

evaluation of tablets. The prepared tablets were evaluated

for various official and non-official specifications:

• Weight variation. Twenty tablets were randomly selected,

and the average weight was calculated. Then, the indi-

vidual tablets were weighed and the individual weight was

compared with the average weight.

• Hardness. Tablets were evaluated for hardness using the

Monsanto hardness tester. Each tablet was placed in con-

tact with the tester’s lower plunger, and a zero reading

was taken. The upper plunger was then forced against a

spring by turning a threaded bolt until the tablet fractured.

1.00

0.50

0.00

-0.50

-1.00

B:B

A:A

R1

-1.00 -0.50 0.00 0.50 1.00

100

90

80

70

60

50

1.00 1.00

0.50 0.50

0.00 0.00

-0.50 -0.50

-1.00 -1.00

A:AB:B

R1

Figure 1: Contour plot for levocetirizine dihydrochloride.

Figure 2: 3-D response surface for levocetirizine

dihydrochloride.A

ll

fig

ur

es

Ar

e c

ou

rt

es

y o

f t

he

Au

th

or

s.

Table III: Optimization of drug-resin ratio.

Amount of bound drug Percent of bound drug

S. No. Ratio

(Drug: Resin)

Levocetirizine

dihydrochloride

Montelukast

sodium

Levocetirizine

dihydrochloride

Montelukast

sodium

1 1:1 14.093 29.924 93.953 99.746

2 1:2 13.700 29.968 91.330 99.893

3 1:3 14.228 29.999 94.853 99.997

4 1:4 14.110 29.89 94.068 99.63

5 1:5 14.208 29.952 94.72 99.84

6 1:6 13.571 29.951 90.473 99.837


Taste Masking

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The force of fracture was recorded and the zero force

reading was subtracted from it.

• Friability. Twenty tablets were weighed and placed in a

Roche friabilator, and the apparatus was rotated at 25 rpm

for 4 min. The tablets were then dusted and weighed.

The friability is given by the formula:

F= (1-W/W0) × 100

Where

W0 = weight of the tablets

before test

W= weight of the tablets

after test

• Water absorption ratio. A piece

of tissue paper folded twice was

placed in a small petri dish con-

taining 6 mL of water. A tablet

was put on the tissue paper and

allowed to wet completely. The

wetted tablet was then weighed.

Water absorption ratio, R was

determined using fo l lowing

equation:

R= 100 x (Wa – W

b)/ W

b

Where

Wb = weight of tablet

before water absorption

Wa = weight of tablet after

water absorption

• Wetting time. A piece of tissue

paper (10.75 × 12 mm), folded

twice, was placed in a culture

dish containing 6 mL of water. A

tablet was put on the paper and

the time for complete wetting

was measured (12).

• Drug content. Ten tablets were

weighed and the average weight

was calculated. The tablets were

then powdered, and a quantity of powder equivalent to

5 mg of levocetirizine dihydrochloride and 10 mg of mon-

telukast sodium was dissolved in 100 mL of 0.1 N hydro-

chloric acid. The amount of levocetirizine dihydrochloride

and montelukast sodium was then determined by HPLC.

• In-vitro disintegration time. Six tablets were placed in a

disintegration apparatus containing distilled water main-

tained at 37 °C ± 2 °C. The time required for the tablet

Table IV: Analysis of variance of the regression (percent drug-resin complex).

Levocetirizine dihydrochloride Montelukast sodium

Total Regression Residual Total Regression Residual

Degree of freedom 14 9 5 14 3 11

Sum of squares 17062.25 15964.35 1097.90 3512.37 1939.2 1573.17

Mean square - 1554.24 219.58 - 503.38 143.02

F - 8.08 - - 4.52 -

F-significance - 0.0166* - - 0.0268* -

*Values of “Prob> F” less than 0.0500 indicate model terms are significant.



Taste Masking

to disintegrate completely, without any palpable mass

remaining in the apparatus, was recorded.

• In-vitro dissolution rate study of ODTs. Drug release

studies were performed using a USP XXII Type I I

tablet dissolution apparatus (LabIndia DS-8000). The

tablet was taken in 900 mL of 0.1 N hydrochloric acid (pH

1.2) with 0.5% sodium lauryl sulfate (SLS). The temperature

and speed of rotation were maintained at 37 ± 0.5 °C and

50 rpm, respectively. 10-mL samples were withdrawn at

15-min intervals, filtered in a nylon filter, and analyzed by

HPLC at 240 nm directly or after appropriate dilution. The

cumulative percent drug release was calculated.

• Taste evaluation study. A bitterness evaluation test was

performed to compare the bitterness of the tablet to

that of each of the pure drugs,

i.e.,levocetirizine dihydrochloride

and montelukast sodium.

Results and discussion

Optimization of drug-to-resin

ratio. The drug resin ratio of 1:3 was

found to show the maximum binding

of drug with the resin. Therefore, the

ratio 1:3 was selected for further

study of various process parameters.

The results are tabulated in Table III.

Optimization of process param-

eters. Fifteen DRC formulations

(F1–F15) of DRC were prepared and

tested. Percent drug release was

found to be minimum at extreme pH

values (i.e., pH of 1.2 and pH 6.8) and

at high level of swelling time (X2). The

maximum drug release was found at

pH 4.0, at high levels of stirring time,

even at low levels of swelling time. These results suggest that

high levels of stirring are required for maximum binding of the

drug with the resin. The release of the drug also depends upon

the pH of the medium. The multiple linear regression (MLR)

for % DRC of levocetirizine dihydrochloride and montelukast

sodium is given in Table I. The model, developed from MLR to

estimate effect (Y1 and Y

2) can be presented mathematically as:

Y1 = 67.24 – 6.78 X

1 + 1.48 X

2 + 3.93 X

3 + 3.97 X

1X

2 + 0.99

X1X

3 – 0.35 X

2X

3 + 6.72 X

1 2 + 6.06 X

2

2 – 62.70 X3 2

Y2 = 31.03 – 6.07 X

1 + 14.32 X

2 – 0.67 X

3,

Where

Y1 = % cumulat ive drug re lease of levocet ir iz ine

dihydrochloride

0

-2

-4

-6

-8

-10

-12

-14

226

224

222

220

218

216

214

Exo up Universal V4.5A TA Instruments

224.92ºC-12.60W/g

207.01ºC207.01ºC-1.516W/g

235.67ºC-1.107W/g

235.67ºC

0 50

-5 0 5 10 15 20

Purity: 86.19 mol %Melting point: 224.96ºC (determined)Depression: 1.16ºCDelta H: 244.7kJ/mol (corrected)Correction: 10.60%Molecular weight: 461.8g/molCell constant: 1.228Onset slope: -16.76mW/ºCRMS deviation: 0.03ºC

100 150Temperature (ºC)

Total area / Partical area

Tem

pera

ture

(ºC

)

200 250 300

Heat

fo

w (

W/g

)

Figure 5: Differential scanning calorimetry thermogram of levocetirizine

dihydrochloride.

1.00

0.50

0.00

-0.50

-1.00

B:B

A:A

R1

-1.00 -0.50 0.00 0.50 1.00

Figure 3: Contour plot for montelukast sodium.

70

60

50

40

30

20

10

R1

1.00 1.00

0.50 0.50

0.00 0.00

-0.50 -0.50

-1.00 -1.00B:B A:A

Figure 4: 3-D response surface for montelukast sodium.



Taste Masking

Y2 = % cumulative drug release of

montelukast sodium

X1 = swelling time

X2 = stirring time

X3 = pH

X1X

2, X

1X

3, X

2X

3 show s t he

interaction term and X1

2, X2

2, X3

2

shows the quadratic relationship

term.

Batch F3 was se lec ted as

o p t i m u m b a t c h f o r f u r t h e r

formulation of ODTs. ANOVA was

applied on cumulative percentages

of drug released to study the fitting

and significance of model. The

F-test of equality for two variances

was carried out to compare the

regression mean square with the

residual mean square (see Table

IV ) for levocetirizine dihydrochloride and montelukast

sodium. The ratio F = 8.08 in the case of levocetirizine

dihydrochloride and F = 4.52 in the case of montelukast

sodium showed regression to be significant.

The estimated model, therefore, may be used as response

surface for the % CDR, as shown by

contour plots in Figures 1 and 2

and 3-D surface in Figures 3 and 4.

Characterization of optimized

drug-resin complex. Differential

s c a n n i n g c a l o r i m et r y (D SC) .

Results from DSC analyses of

the pure drugs, levocetir izine

dihydrochloride and montelukast

sodium, are shown in Figures 5

and 6. DSC analyses of the dual-

drug resinate showed significant

decrease in melt ing point of

the pure drugs. DSC confirmed

the interaction of formulation

constituents with levocetirizine

dihydrochloride and montelukast

sodium and, therefore, decrease in

the melting point.

FTIR Spectrum. FTIR spectra of

pure levocetirizine dihydrochloride

and montelukast sodium showed

characteristics peaks. A minor

shifting of functional peaks was

observed in the physical mixture

of these drugs (see Table V ).

New peaks and major shifts of

the functional peaks in the FTIR

spectrum of batch F3 confirmed

the formation of complex.

In-vitro dissolution rate study of DRC in 0.1 N HCl

and in phosphate buffer pH 6.8. In-vitro release studies

of the optimized formulation were carried out in 0.1 N

HCl (pH 1.2) and in phosphate buffer (pH 6.8), both with

0.5% SLS. Levocetirizine dihydrochloride showed 99.19%

0.5

0.00

-0.5

-1.0

-1.5

-2.0

He

at

fo

w (

W/g

)

Exo up Universal V4.5A TA Instruments

0 50 100 150Temperature (ºC)

200 250 300

178.8

178.6

178.4

178.2

178.0

177.8

Tem

pe

ratu

re (

ºC)

-50 0 50 100 150 200Total area / Partical area

178.71ºC-1.556W/g

181.21ºC-0.5729W/g

181.93ºC

Figure 6: Differential scanning calorimetry thermogram of montelukast sodium.



Taste Masking

and95.87%, while montelukast sodium showed 65.84% and

84.49% release in 0.1 N HCl and phosphate buffer (pH 6.8),

respectively. The result is shown graphically in Figure 7.

Sensory evaluation for bitterness of DRC. The sensory

evaluation of the formulation showed that the resinate’s

taste was more acceptable to the test volunteers than that

of the pure drugs.

Evaluation of ODT. The micromeritic properties of the

powder blend were evaluated and the results are tabulated

in Table VI.

After the micromeritic studies, ODT were evaluated

for various parameters (e.g., weight variation, hardness,

friability, water absorption ratio, wetting time, drug content,

disintegration time, and in-vitro drug release). The results

are tabulated in Table VII.

The ODTs were found to pass the weight variation test

as per I.P. (150 ± 7.5). The hardness was found to be 4.1 kg/

cm3, which is sufficient to withstand mechanical shocks of

handling in manufacture, packaging, and transportation. The

friability was 0.76% and disintegration time was found to

be 47 sec, which is acceptable. The water absorption ratio

was found to be 75.90. The wetting time was found to be 35

seconds, and drug content was 98% for levocetirizine and

95% for montelukast.

In-vitro dissolution rate study of ODTs. In-vitro drug

release studies were performed in two different dissolution

media, simulated gastric fluid and phosphate buffer of

pH 6.8, and results were compared with those for the

commercial formulation (tablet) in the same media. In

simulated gastric fluid, ODT showed 99.64% and 54.85%

release for levocetirizine dihydrochloride and montelukast

sodium respectively, whereas the release values for the

marketed formulation were 93.86% for levocetirizine

dihydrochloride and 48.17% for montelukast sodium. In

phosphate buffer of pH 6.8, the ODT showed 90.28% release

for levocetirizine dihydrochloride and 75.57% release for

montelukast sodium. Comparable values in the commercial

formulation were 75.12% for levocetirizine dihydrochloride

and 75.55% for montelukast sodium. The results are shown

graphically in Figures 8 and 9.

Conclusion

Using complexation with ion-exchange resin and the Box-

Behnken model for optimizing the complexes, the taste of

levocetirizine dihydrochloride and montelukast sodium was

effectively masked. Taste masking was optimized based on

such parameters as stirring time, pH effect, and swelling

time of resin. The maximum drug release was found at

Table V: Fourier Transform Infrared (FTIR) data (peak at cm-1) of levocetrizine hydrochloride, montelukast sodium,

physical mixture and optimized formulation (F3).

Levocetirizine

dihydrochloride

Montelukast sodium Physical mixture Optimized formulation

(F3)

Interpretation

3020.53 2927.94 3147.833132.4, 2927.94,

2854.65Aromatic stretch

1735.93 1720.06 1705.07 1697.36 Carbonyl group (C=O)

1492.90 1496.76 1500.62 1500.62 C=C

1400.32 1400.32 1400.32 1400.32 C-X

1184.29 1130.29 1145.72 1145.71 C-O

1138.00 1018.41 964.41 1018.41 C-N

Table VI: Evaluation of micromeritic properties of the

powder blend.

S. No. Parameter Result

1. Angle of repose (degrees) 30.45

2. Bulk density (g/cm3) 0.46

3. Tapped density (g/cm3) 0.52

4. Compressibility index (%) 9.80

5. Hausner’s ratio 0.90

6. Flowability Excellent

Table VII: Evaluation of orally disintegrating tablets.

S. No. Parameter Result

1. Weight variation Pass

2. Hardness (kg/cm3) 4.1±0.2

3. Friability (%) 0.76±0.02

4. Water absorption ratio 75.90

5. Wetting time (sec) 35

6. Drug content (%)

98% (Levocetirizine

dihydrochloride) &

95% (Montelukast sodium)

7. Disintegration time (sec) 47±0.3


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P.O. Box · CH-5033 Buchs, Switzerland

Phone: +41 62 834 55 55 · Fax: +41 62 8345500

E-mail: [email protected]

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Vertriebsgesellschaft mbH

P.O. Box 1611 · D-71306 Waiblingen, Germany

Phone: +49 7151 95811-0 · Fax: +49 7151 15526


rommelag USA, Inc.

27905 Meadow Drive, Suite 9

Evergreen CO 80439, USA

Phone: +1.303. 674.8333 · Fax: +1.303.670.2666

E-Mail: [email protected]

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Taste Masking

high values of stirring time,

even at low values of swelling

time. DSC and FTIR analyses

confirmed the drug complex

formation. The taste of the

resulting complex was found

to be palatable.

R e s u l t s s u g g e s t t h a t

the mathemat ica l model

developed in the present study

can be applied to formulate

a taste-masked drug resin

complex for different drugs.

Retrospectively, a dual-drug

resinate of desired release

characteristics can also be

developed. ODTs formulated

using crosspovidone and

sod ium s tarch g l yco la te

showed faster disintegration

and enhanced drug release.

The ODTs showed bet ter

release when compared with

the commercial formulation.

These formulations can be

considered for scaleup.

References

1. A. Legin et al., Anal. Bioanal. Chem.

380 (1) 36-45 (2004).

2. T.H.T. Hoang et al., Int. J. Pharm.

434 (1-2) 235-42 (2012).

3. V. Sayeed et al., “Solid Dosages

and Excipients 2015” eBook sup-

plement to Pharm. Tech. p. 12.

(2015).

4. H. Sohi, Y. Sultana, and R.K. Khar,

Drug. Dev. Ind. Pharm. 30 (5)

429-48 (2004).

5. A. Helmy et al., J. of American

Science. 7 (12) 831-44 (2011).

6. V. Anand et al., Drug Discov. Today.

6 (17) 905-14 (2001).

7. I. Singh et al., J. Pharm. Sci. 32 (2)

91-100 (2007).

8. H. X. Zeng et al., Drug. Dev. Ind.

Pharm. 37 (2) 201-7 (2001).

9. R. Sheshala et al., Arch. Pharm.

Res. 34 (11) 1945-56 (2011).

10. www.rxlist.com, accessed on

14/10/12.

11. D. Shukla et al., Chem. Pharm. Bull.

57 (4) 337-45 (2009).

12. H. Sunada et al., Powder. Technol.

122 (2) 188-98 (2002). PTE

120

100

80

60

40

20

0

100

90

80

70

60

50

40

30

20

10

0

% d

rug

rele

ase

in

sim

ula

ted

gast

ric

fu

id

0 20 40

Levocetirizine dihydrochloride ODT Levocetirizine dihydrochloride ODT

Levocetirizine dihydrochloride marketed

formulationLevocetirizine dihydrochloride marketed

formulation

60 80

Time (min.)

0 20 40 60 80

Time (min.)% d

rug

rele

ase

in

ph

osp

hate

bu

ffer

pH

6.8

60

50

40

30

20

10

0

80

70

60

50

40

30

20

10

0

% d

rug

re

lea

se i

n s

imu

late

d g

ast

ric

fu

id

0 20 40

Montelukast sodium ODT

Monelukast sodium marketed formulation

Montelukast sodium ODT

Monelukast sodium marketed formulation

60 80

Time (min.)

0 20 40 60 80

Time (min.)

% d

rug

re

lea

se i

n p

ho

sph

ate

bu

ffe

r p

H 6

.8

Figure 8: Comparative percent release of levocetirizine dihydrochloride in simulated

gastric fluid and in phosphate buffer pH 6.8.

Figure 9: Comparative percent release of montelukast sodium in simulated gastric

fluid and in phosphate buffer pH 6.8

120

100

80

60

40

20

0

120

100

80

60

40

20

0

0 20 40

Levocetirizine Montelukast

60 80

Time (min.)

0 20 40

Levocetirizine Montelukast

60 80

Time (min.)

% d

rug

rele

ase

in

sim

ula

ted

gast

ric

fu

id

% d

rug

rele

ase

in

ph

osp

hate

bu

ffer

pH

6.8

Figure 7: Cumulative percent drug release of F3 in simulated gastric fluid (left) and

phosphate buffer pH 6.8 (right).


API SyntheSIS & MAnufActurIngM

ich

ae

l B

an

ks/

Ge

ttyIm

ag

es

Many transformations that afford important

categories of organic building blocks useful

for the synthesis of pharmaceutical intermediates

and APIs cannot be performed due to hazardous

conditions. Reactions that require the use of unstable

reagents lead to the formation of highly reactive

intermediates, and those that are highly exothermic

typically are not suitable for implementation on a large

scale because of the hazards they pose.

Research is ongoing in both the industrial and

academic setting to develop alternative approaches

that will enable these transformations to be performed

safely on a commercial scale. Such approaches include

the development of new forms of hazardous reagents

that are stable and can be readily manipulated in the

plant setting; identification of new reaction conditions,

such as the use of flow chemistry, to reduce the

quantities of hazardous reagents and/or provide

highly controlled conditions for energetic reactions;

and the identification of entirely new routes that do

not have any of these issues. Selected examples of

recent approaches designed to overcome hazardous

transformations are described in the following sections.

the benefits of flow chemistryIn the Vilsmeier (or Vilsmeier–Hack) reaction,

aryl aldehydes and ketones are obtained from

substituted amides via their reaction with

phosphorous oxychloride and electron-rich aromatic

compounds. The substituted chloroiminium ion

formed from the reaction of the substituted amide

with phosphorous oxychloride is referred to as

the Vilsmeier reagent (VR). While this reaction

can provide a wide range of interesting carbonyl

compounds, its use on a large scale can be difficult,

because VRs are often irritants and also hazardous

reagents due to their high thermal energies of

decomposition. Researchers at Novartis Pharma

employed flow chemistry to address this issue (1).

They achieved the in-line formation and immediate

consumption of VRs using a combination of batch

and flow technologies and applied the new process

to the synthesis of the anti-diabetic drug vildagliptin.

Researchers at AMRI also performed a potentially

hazardous cyclopropane ring-opening reaction in

a continuous-flow reactor to increase the safety

of the process (2). Subsequent copper-mediated

Diels–Alder and palladium-catalyzed Negishi coupling

reactions were also used in the optimized synthesis of

taxadienone on a decagram scale.

At Bristol-Myers Squibb, a hazardous analysis of a

reaction involving the conversion of a tertiary alcohol

to a hydroxypyrrolotriazine intermediate identified

the potential for thermal runaway (3). To mitigate

this potential, a continuous oxidative rearrangement

process was developed that involves the mixing of

three different, stable feed streams in a specific

order using in-line static mixers. A “plug flow” design

achieved using heat exchangers ensures sufficient

residence times for completion of the reaction. The

continuous process has been employed on the pilot

plant and commercial manufacturing scales for the

production of the investigational liver cancer drug

brivanib alaninate.

Increasing safety with PAtAdvances in process analytical technology (PAT)

not only help speed up process development and

optimization, they can also facilitate the control,

and thus increase the safety, of synthetic organic

reactions. Researchers at Merck Sharp & Dohme

recently reported the successful application of PAT

for determining the appropriate timing of reagent

addition and reaction quenching (4). The technologies

discussed included process video microscopy (PVM),

a new focused-beam reflectance measurement

(FBRM) method, miniature process infrared (IR)

spectroscopy, and a flow IR sensor. PVM was used

as a nondestructive method for analyzing particle

morphologies in real time, while the new FBRM

technique has improved reliability due to its greater

resistance to probe fouling. The miniaturized IR

system was found to be easier to use at scale-up and

more robust, and the miniature IR flow sensor was a

more cost-effective tool with a faster response, and

thus useful for continuous flow processes.

The IQ Consortium, an organization of

pharmaceutical and biotechnology companies

with the mission of advancing science-based and

scientifically-driven standards and regulations

for pharmaceutical and biotechnology products

worldwide, also recently reported on the current

Safer reagents and reaction conditions are making many hazardous transformations possible.

New Ways Around Hazardous Reagent Chemistry

cynthia A. challener, PhD,

is a contributing editor to

Pharmaceutical Technology

Europe.



API Synthesis & Manufacturing

state of PAT use in the development

of APIs (5). In the paper, the authors

point out that PAT can minimize the

hazards posed to operators when

sampling hazardous materials and

also provide more reliable data on

processes that involve the use of

hazardous materials. Through greater

process understanding, increased

process control—often through the

use of simplified monitoring and

control systems—is possible at the

commercial production scale.

Surrogates with better safety profilesOne of the most effective methods for

eliminating the concerns associated

with hazardous reagents is to

develop stable derivatives or totally

new alternatives that accomplish

the desired transformation without

the safety concerns of the original

compounds. Several examples have

appeared in literature recently.

Michael Willis at the University of

Oxford developed a method for the

synthesis of sulfonamides via in situ

formation of intermediate sulfinates

from magnesium-, lithium-, and

zinc-based reagents and DABSO,

a surrogate for sulfur dioxide (6).

The sulfinates were reacted with

N-chloroamines, which were

also generated in situ by reacting

amines with aqueous bleach. While

sulfonamide groups are present in

biologically relevant compounds,

they are often accessed through the

corresponding sulfonyl chlorides,

which can be unstable. The new

method provides a route that avoids

sulfanyl chlorides. Primary and

secondary amines, anilines, and

amino acids were all suitable for the

reaction, which proceeded most

efficiently with Grignard reagents.

Sodium metal is often used

effectively for Birch reductions and

the reduction of esters (Bouveault–

Blanc reduction), but does have

associated safety concerns at larger

scale given the pyrophoric nature

of sodium metal and the volatility of

ethanol. Researchers at the University

of Manchester and Pentagon Fine

Chemicals reported that a dispersion

of sodium metal particles with

diameters ranging from 5–15 μm

in a mineral oil is a nonpyrophoric,

free-flowing powder alternative that

can be handled in air and provides

results similar to sodium metal (7).

In particular, the Bouveault–Blanc

reduction was found to proceed in

high yields at 0 °C in hexane for a wide

range of aliphatic ester substrates with

2.5 equivalents of isopropanol rather

than ethanol and just 4.5 equivalents

of the sodium dispersion. Notably,

alkenes, aryl amines and fluorides,

acidic protons, and sterically hindered

carbon centres were tolerated.

Direct aryl C-H chlorination is

another desirable reaction for the

preparation of aromatic chlorides,

but the most reactive methods

typically require the use of hazardous

reagents such as chlorine (Cl2) or

sulfuryl chloride (SO2Cl

2). Milder

reagents are available, including

N-chlorosuccinimide (NCS) and

1,3-dichloro-5,5-dimethylhydantoin

(DCDMH), but their applicability

is limited due to their reduced

reactivity. Other reagents that

have been employed also suffer

from unattractive features such as

toxicity, hydroscopicity, light/heat

sensitivity, and explosive properties

among others. Phil S. Baran and

colleagues at The Scripps Research

Institute and Bristol-Myers Squibb

have developed the guanidine-based

chlorinating reagent 2-chloro-1,3-

bis(methoxycarbonyl)guanidine

(CBMG), which they refer to as

Palau’chlor, as an alternative for the

mild and safe direct chlorination of

nitrogen-containing heterocycles

and certain arenes, conjugated

π-systems, sulfonamides, and silyl

enol ethers (8). The new reagent is

an air-stable solid that is thermally

stable below 100 °C, yet achieves

transformations that have only been

possible in the past with highly

reactive, hazardous chlorinating

reagents. Importantly, the cost of

the reagent and its functional group

tolerability are similar to that of NCS.

references1. L. Pellegatti and J. Sedelmeier, Org.

Process Res. Dev. 19 (4) 551–554 (2015).

2. S. G. Krasutsky, et al., Org. Process Res.

Dev. 19 (1) 284–289 2015.

3. Thomas L. LaPorte, et al., Org. Process

Res. Dev. 18 (11) 1492–1502 (2014).

4. George Zhou, et al., Org. Process Res.

Dev. 19 (1) 227–235 (2015).

5. John D. Orr, et al., Org. Process Res.

Dev. 19 (1) 63–83 (2015).

6. M.C. Willis, et al., Angew. Chem., Int.

Ed. Engl. 54 (4) 1168-1171 (2015)

7. D.J. Proctor, et al., J. Org. Chem. 79 (14)

6743-6747 (2014).

8. Phil S. Baran, et al., J. Am. Chem. Soc.

136 (19) 6908-6911 (2014). Pte

Rx-360, an international, non-profit supply chain consortium, has

formed the Rx-360 Asia Working GroupçIndia to identify and

mitigate root causes of quality problems and supply chain

security. The group will be led by Anish Swadi, vice-president,

business development at Hikal; Huzefa Hussain, manager-quality

assurance at Amgen; and Prashant Wani, senior supplier auditor

at Eli Lilly & Company.

The Rx-360 Working Group–Asia has operated in Shanghai for

two years; Rx-360 reports that it developed a presence in India

given the size of the pharma market and its importance as a

manufacturer and exporter of APIs and drug product to North

America and Europe. As a neutral, open, and consensus-building

industry forum, Rx-360 seeks to help address quality challenges

and support India industry.

The working group’s goals are to build Rx-360’s reputation and

credibility in India as a group with tools to solve problems relevant to

the global pharma industry and supply chain; help understand and

mitigate root causes of the most pressing quality challenges; share

best practices and case studies from sites; spread awareness and

understanding about Rx-360, its activities, and its audit programmes

among India-based suppliers and manufacturers; and position

Rx-360 as a mentoring resource for the India pharma industry.

The Rx-360 India Working Group has prepared a survey to solicit

feedback from individuals who may have encountered data

integrity issues at GMP sites located in India. The survey will

benchmark strategies for educational materials and other efforts

to advance data integrity understanding and mitigations, the

organization reports.

rx-360 establishes working group in India

42 Pharmaceutical Technology Europe JunE 2015 Pharmtech.com

ES619408_PTE0615_042.pgs 05.23.2015 02:52 ADV blackyellowmagenta

Product/Service ProfileS

catalent Pharma Solutions

Catalent Pharma Solutions, a global

leader for drug product development

and manufacturing, provides a broad

range of inhalation solutions.

Catalent’s inhalation offer integrates the

company’s knowledge and experience in

preformulation sciences, formulation

development, device evaluation/selection,

performance testing, CMC, and

manufacturing to reliably deliver all relevant

dosage forms. These include:

•Pressurized metered dose

inhalers (pMDIs)

•Dry powder inhaler (DPIs)

•Nasal spray

•Solutions/suspensions for inhalation

For more than 40 years, Catalent’s deep

expertise, end-to-end solutions, and reliable

execution have been successfully applied to

all primary inhaled dosage forms to accelerate

drug development programmes and bring

better treatments to patients worldwide.

The acquisition of Micron Technologies’

particle size engineering capabilities has

expanded Catalent’s solution toolkit in the

development, evaluation, and manufacture

of inhalation products to accelerate and

advance molecules and programmes from

early development through to commercial

manufacturing.

catalent Pharma Solutions

www.catalent.com

[email protected]

Powder flow tester

Brookfeld Powder Flow Tester:

Small Samples … No Problem!

Brookfeld’s Powder Flow Tester offers a

solution for small powder samples. Perfect

for pharmaceutical formulators who test

expensive powders in limited quantities, the

new Small Volume Shear Cell requires only

43cc of powder. Other good candidates

include materials, which are diffcult or

messy to handle, such as powdered inks.

The Small Volume Shear Cell has an added

technical performance advantage, namely

the ability to generate higher consolidation

stresses, which simulates conditions in

larger bins and silos.

The Brookfeld PFT Powder Flow Tester

provides quick and easy analysis of powder

fow behaviour in industrial processing

equipment. The PFT allows technicians to

QC check incoming materials and evaluate

how powders will discharge from storage

containers. The operator can also rapidly

characterize new formulations for

fowability and adjust composition to match

the fow behavior of established products.

Brookfeld engineering laboratories, inc.

www.brookfeldengineering.com/products/pft/powder-fow-tester.asp

[email protected]

catalent pMdi Manufacturing facility,

Morrisville, Nc

triS AMiNo® Products

Based on ANGUS’s exclusive nitroalkane

chemistry, ANGUS TRIS AMINO® products

are excellent buffers, neutralizers,

solubilizers and stabilizers for life science

formulations and processes. They are

water, alcohol and glycol soluble and

suitable for a wide range of uses. ANGUS

is the only back integrated manufacturer

of cGMP certifed TRIS AMINO, and our

commitment to best-in-class operating

performance ensures a consistent supply

of high-quality product that meets the

most stringent specifcations. Like all of

our specialty additives, our TRIS AMINO

products are fully supported with localized

technical expertise, regulatory assistance

and formulation guidance from our global

network of Customer Application Centers.

ANGuS chemical company

angus.com

[email protected]



combino Pharm contract

Manufacturing

The strategic location of Combino Pharm’s

manufacturing facility in Malta, an EU

patent-free country, allows our clients to

manufacture and stockpile their products

during the valid term of the patent in

Europe, and launch them the frst day after

the patent’s expiration date. This provides

the great opportunity to be the frst in the

EU market, a huge advantage when

compared to other competitors.

contract Manufacturing Services•Manufacturing of products in solid

dosage form

•Packaging services

•Pharmaceutical product development

•Raw materials testing

• IP assessment

•Regulatory affairs support

•Procurement support

•Additionally, we offer services by

The Maltese Release Company

o Analysis of finished products

o Transfer and/or full validation of

analytical methods

o Audits to third parties

o Stability studies

o Stockpiling / Sampling

o Product importation

o Product release (EU-GMP)

combino Pharm S.l.

www.combino-pharm.com

[email protected]

Syncade—electronic

Batch records

Emerson’s Electronic Batch Records

solution within Syncade, delivers reliable

product quality through right frst time

production. Pharmaceutical manufacturers

require repeatable production processes

regardless of whether they are executing

manual or automated production steps.

Syncade’s Electronic Batch Records

brings together electronic and manual

activities in a single environment

through integrated workfows to provide

consistent and reproducible production.

Operators are guided through the

production steps eliminating the variability

associated with manual processes.

Electronic Batch Records delivers a

complete record of your batch production

using information collected directly from

your production processes. This eliminates

incorrect data entry and allows you to link

directly to production steps to get accurate

data. Review by exception further expedites

the quality review process, reducing

approval time allowing you to release

product faster.

emerson Process Management

www.emersonprocess.com

[email protected]

etQ compliance

Management Software

EtQ is the leading FDA Compliance, Quality,

EHS and Operational Risk Management

software provider for identifying, mitigating

and preventing high-risk events through

integration, automation and collaboration.

Founded in 1992, EtQ has always had a

unique knowledge of FDA Compliance,

Quality, EHS and Operational Risk processes,

and strives to make overall compliance

operations and management systems

better for businesses. EtQ is headquartered

in Farmingdale, NY, with main offces

located in the US and Europe. EtQ has been

providing software solutions to a variety

of markets for more than 20 years. For

more information, please visit http://www.

etq.com or contact us at 800.354.4476.

etQ

www.etq.com

[email protected]

Product/Service ProfileS

44 Pharmaceutical Technology Europe June 2015 Pharmtech.com


Product/Service ProfileSProduct/Service ProfileS

Müller containment

valve Mcv

transferring highly potent or toxic

substances?

New generation of Müller containment

valve

Whether operated manually or

automatically, the Müller Containment Valve

MCV ensures that your products transfer

safely. The new valve generation is suitable

up to OEB Level 5 (SMEPAC), i.e. up to

OEL < 1µg/m³. The valve can be cleaned

without removing the seals and there

is no product trapped between body

and valve seat. The new construction is

lightweight, compact and self-locking.

The locking mechanism is smooth

running but powerful with no rollers or

bolts—there is no mechanical wear.

You can choose between valve sizes DN

65, 100, DN 150, DN 200 and DN 250.

Müller GmbH

www.mueller-gmbh.com

[email protected]

SP270 and AdvANciA

Nemera is one of the world leaders in the

design, development and manufacturing

of drug delivery solutions. Its expertise

covers multiple modes of delivery: nasal,

buccal, auricular (sprays pumps and valves),

but also ophthalmic (preservative free

droppers), pulmonary (inhalers), dermal

and transdermal (dispensers), parenteral

(injectors, pens, safety devices). Nemera

provides solutions for the pharmaceutical

industry, including standard innovative

products, development of custom

devices and contract manufacturing.

In particular, Nemera proposes a wide

range of pumps for ENT delivery solutions.

After the SP270, our standard spray pump

for ear, nose and throat, Nemera has

developed Advancia®, the latest breed of

user independent nasal spray platform for

pharmaceutical industry. Advancia® offers a

new alternative to improve treatment

compliance in an increasingly demanding

nasal spray market.

Nemera relies on its regulatory expertise

to support customers and manufactures in

strict compliance with GMPs to meet the

highest standards of quality, safety, and

consistency.

NeMerA

www.nemera.net

[email protected]

Bio/Pharmaceutical GMP

Product testing

Eurofns BioPharma Product Testing offers

the most complete range of testing

services, harmonized quality systems and

LIMS to more than 800 virtual and large

pharmaceutical, biopharmaceutical and

medical device companies worldwide.

We offer complete CMC Testing Services

for the Bio/Pharmaceutical industry,

including all starting material, process

intermediates, drug substance, drug

product and manufacturing support, as well

as broad technical expertise in

Biochemistry, Molecular & Cell Biology,

Virology, Chemistry and Microbiology.

With a global capacity of more than

50,000 square meters and 14 facilities

located in Belgium, Denmark, France,

Germany, Ireland, Italy, Spain, Sweden and

the US, our network of GMP laboratories

and vast experience allow us to support

projects of any size from conception to

market. Further, we have teams of

scientists placed at more than 40 client

facilities throughout Europe and the U.S.

through our award-winning Professional

Scientifc Services (PSS) insourcing program.

eurofns BioPharma Product testing

www.eurofns.com/Biopharma

[email protected]




bottelpack® 430—compact

blow-fill-seal technology

What is expected from a compact and

f exible laboratory BFS machine? A minimal

mould size to keep the costs for trials and

stability tests, etc. with various mould

tools low and also the advantages provided

by the rotation machine technology

(continuous parison, little plastic waste) of

the popular bottelpack® 460/461 models.

The result of this mix is the bottelpack®

430—a combined shuttle and rotation

machine. The basic principle of the rotation

machine technology with a continuous,

extruded, uncut parison forms the basis

for this machine. The mould follows the

continuously extruded parison during the

blow-f ll-seal process. Once the mould

has been opened, it cycles back and is

positioned directly above the recently

produced ampoule bar to shape the next

block. This creates a continuous ampoule

strip that is fed into an external punch. The

bottelpack® 430 is ideal as a laboratory

machine and also for small batch sizes.

rommelag ag

www.rommelag.com

[email protected]

excipients and raw Materials

for Pharmaceutical and

Biopharmaceutical production

Since the beginning, PanReac AppliChem

has played an important role in the

pharmaceutical and biopharmaceutical

industries, producing and supplying

the best raw materials to be used in

manufacturing process or as excipients

in the f nal formulation.

PanReac AppliChem has an integrated

management system implemented in all

activities relevant to the following standards:

IPEC/PQG GMP Guide, ISO 9001:2008, ISO

14001:2004 and OHSAS 18001:2007.

Our Quality Control Laboratories, f tted

with the latest technologies, analyse and

guarantee all products comply with the

specif cations of Pharmacopeia. From raw

materials to f nal products, we ensure our

products are safe across the entire value

chain.

Pharma grade product range meets the

specif cations def ned in the latest version

of uSP and Ph. eur., among other

pharmacopeias. BioChemica and Cell

Culture grade guarantee stable and

consistent biopharmaceutical production

process (upstream).

For further information meet us at CPhI

Worldwide 2015, Madrid 13–15 October,

Hall 7 stand 5K16.

Panreac Applichem

www.panreac.com,www.applichem.com

[email protected]

oPtiMA pharma for

uncompromising

pharmaceutical applications

Optima Pharma develops and manufactures

f lling, sealing and process technology for

pharmaceuticals. Highly sophisticated,

fully automated systems from Optima

Pharma are used to process blood plasma

products, vaccines, oncology and biotech

products in pref lled syringes, vials, IV

bottles and cartridges. In addition to f lling

and sealing, complementary functions

and process equipment are integrated,

including washing machines, sterilization

tunnels and containment systems.

Pharmaceutical freeze drying and robotic

product handling complete the company’s

extensive portfolio. The division guarantees

quick, professional service with 13

international locations. Optima Pharma is

a member of the OPTIMA packaging group

GmbH (Schwäbisch Hall), which employs

a workforce of 1,900 around the globe.

oPtiMA pharma GmbH

www.optima-pharma.com

[email protected]

46 Pharmaceutical Technology Europe June 2015 Pharmtech.com



NovaPure® components

West NovaPure® elastomeric components

are formulated and manufactured

using a QbD approach that takes

into consideration the entire supply

chain from raw materials through

distribution and drug packaging. Quality

characteristics are engineered to meet

the requirements of the pharmaceutical

manufacturer and help promote protection/

compatibility of drug product.

The following important QbD elements

were used to develop and produce NovaPure

components with a commitment toward

enhancing drug product quality:

•Quality Target Product Profile (QTPP)

•Critical Quality Attribute (CQA)

•Quality Risk Management (QRM)

•Knowledge Management (KM)

•Critical Process Parameter (CPP)

•Control Strategy (CS)

• Lifecycle Management (LCM)

•Continuous Improvement (CI)

Consideration of all these factors during

development of NovaPure components has

achieved a well-understood component and

robust processes that 1) deliver a component

meeting the QTPP and 2) are controlled by

defned steps within the manufacturing

process. During commercial-scale

manufacturing, the trending of component

performance on a continuous basis provides a

major advantage through early detection of

potential issues and further optimization of

the control strategy to ensure reliable level of

high-quality components.

West Pharmaceutical Services, inc.

www.westpharma.com

[email protected]

lcMS-8060 triple quadrupole

mass spectrometer expands

ufMS family

Shimadzu’s new LCMS-8060 is designed to

push the limits of LC/MS/MS quantitation

for applications requiring highest

sensitivity and robustness to deliver a

meaningful solution for routine LC/MS/

MS analyses. It detects substances at

ultra-trace level or in smallest sample

concentrations which have to be diluted

in order to avoid matrix effects.

The LCMS-8060 combines a heated ESI

source with all UF technologies including

UFsweeper III, a collision cell flled with

argon gas. With the new UF Qarray ion

guide technology increasing ion production

and signal intensity, the LCMS-8060

introduces a new level of sensitivity and

makes a real difference to working better

and faster.

Shimadzu europa GmbH

www.shimadzu.eu

[email protected]

cleanroom documentation

Systems

VAI is proud to introduce a new line of

Cleanroom Documentation Systems.

We have addressed and solved the

challenges surrounding particulate and

fber contamination in controlled areas

from GMP required documentation

by developing, CleanPrint 10, the

Core2Print, and Core2Write.

CleanPrint 10, is the synthetic, cellulose

free, low particulate, writing substrate. It is

extremely durable, yet pliable, while being

resistant to abrasion, chemicals, and ink

smearing. The Core2Print, is a 316L

Stainless Steel HEPA fltered printing

system. The Core2Print prints wirelessly

onto VAI’s pre-sterilized CleanPrint 10 paper

into the controlled area. Core2Write is a line

of custom documentation featuring:

logbooks, ID tags, forms, and labels. All

Core2Write products are printed on

CleanPrint 10 synthetic writing substrate.

Core2Write products available are sterile,

and quadruple bag packaged in VAI ABCD

Cleanroom Introduction System. Each

product is completely customizable, based

on customer specifc requirements, and

offer traceability via barcode or patented

RFID technology.

veltek Associates, inc.

www.sterile.com

[email protected]



Solubility EnhancementSolutions using Predictive Analytics & Molecular Modeling

Register for free at www.pharmtech.com/pt/solubility

This webcast will cover the challenges being faced by the industry due

to the increase in insoluble molecules, and state-of-the-art methods

for identifying and leveraging the best solubilization technology. The

presentation will discuss a new, systematic approach that enables

rapid formulation optimization and process development utilizing

spray drying. Experts will provide examples of how encapsulating

expertise, rigorous scientifc practices, experimental data, and in-sil-

ico simulations into a proprietary solubilization platform can deliver

greater insights and better outcomes. The webcast will include:

n The challenges being faced—along with progress being made—in dealing with insoluble molecules;

n Methodology and video simulations of drug/polymer interactions within a dispersion for optimal excipient selection;

n A case study utilizing this approach from technology selection through dosage form development.

For questions contact Kristen Moore at [email protected]

Sanjay Konagurthu, Ph.D.

Senior Director, Research and

Development,

Patheon

Ryan Minikis

VP Product Development,

Patheon

Matt Wessel, Ph.D.

Senior Director of

Computational Sciences

Patheon

Moderator:

Rita Peters

Editorial Director,

Pharmaceutical Technology

WHO SHOULD ATTEND:

n Process R&D scientists, leaders and managers

n Formulation scientists

n Strategic sourcing directors

n Pharmaceutical sciences project leaders and project managers

n Anyone facing the prospect of seeking help to overcome poor solubility

Sponsored by Presented by

KEY LEARNING OBJECTIVES:

n Key criteria that should be used to select the best solubilization technology;

n How molecular modeling can give greater insights into drug-excipient interactions;

n The benefts of a systematic approach to overcoming poor solubility;

n The use of spray drying to create amorphous solid dispersions.

ON-DEMAND WEBCAST Originally aired June 4, 2015

P R E S E N T E R S


TROUBLESHOOTINGD

AN

LE

AP

/GE

TT

Y I

MA

GE

S

TROUBLESHOOTING

Wash-water parameters, water quality, and

basket loading are important for optimal cleaning.

This article will address common mistakes that

impede the effectiveness of automated washing of,

for example, laboratory glassware or manufacturing

equipment parts. When establishing an effective

cleaning programme, it is important to consider

industry-accepted cleaning factors, which include

temperature, action, chemistry, and time (TACT), as

well as coverage and soil. To appropriately account

for these factors in an automated washing system,

one must select appropriate chemistries and loading

accessories. In addition, there are several common

mistakes that can be avoided.

Common mistakesProtein-based soils. If hot water is used at the

prewash phase when attempting to clean a protein-

based soil, the soil will “bake” onto the surface, which

will make it difficult to remove during the subsequent

wash phase. The solution is to use cold water in the

pre-wash phase when cleaning a protein-based soil.

Oily soils. Using cold or ambient temperature

water during the wash phase when attempting to

clean oily or greasy soils will either increase cycle

time or fail to remove the soil from the surface.

When working with these types of soils, very hot

water should be used in both the prewash and wash

phases of the automated washing process. While it

is important to monitor the water temperature during

prewash and wash, when cleaning greasy soils it is

also important to consider temperature during the

final rinse phase. Performing the final rinse of the

automated washing process with very cold water

will lead to long drying times. It is optimal to use the

highest possible final rinse temperature.

Cleaning chemicals. Consider the appropriate

operating range of water temperatures for the

chemical being used to remove the soil. Check the

manufacturer’s label on the cleaning chemistry for the

recommended water-temperature operation range

to ensure timely and complete removal of a soil. The

chemical’s pH is also crucial. Using chemicals with

the wrong pH can result in either a long wash time or

improper cleaning. It is best to use acidic chemicals

for inorganic, mineral-based soils, and alkaline

chemicals for organic and protein soils. It is also

important to remember that certain types of process

parts or load items might be pH sensitive. Acidic or

alkaline detergents used to clean aluminum parts

or load items, for example, can lead to accelerated

degradation or deterioration of those item surfaces.

When working with these types of substrates, the

best results will usually be achieved by using a

pH-neutral chemistry.

Wash times may be extended if using a lower

detergent concentration for items that are heavily

soiled. In this instance, the detergent concentration

should be increased until a reasonable result/time

ratio is reached.

While it is important to ensure appropriate

detergent concentration, it is also mandatory to

consider the impact of chemistries that will create

foaming in the chamber. Foam will create cavitation

or the formation of vapour cavities in a liquid in

the pump, which can lead to lower water pressure

and potential damage to the pump. Foam can also

negatively impact sensors and probe readings.

Foam can also increase the required volume of rinse

water needed to complete the cleaning process. To

avoid these issues, it is important to use the wash

temperatures and chemicals recommended by the

equipment manufacturer. Non-foaming detergents

can also be used.

Rinse phase. The rinse phase is yet another area

where mistakes can increase overall cycle time.

Setting a long time for a rinse phase will result in a

longer cycle time and lower efficiency. It is best to

shorten overall rinse time and to simply add additional

rinse phases. In addition to reducing the time for

rinse phases, it may be helpful to reduce the rinse

temperature to prevent stress on equipment. High

temperature does not equate to improved rinsing

efficacy. There are certain applications, such as

animal cage processing, where thermal disinfection

is required, and for these the rinse temperature in all

phases must remain high (1).

Water quality. Water quality is crucial to a

successful automated washing process. In instances

where low quality water is used in all phases,

PreventingCommon Mistakes in Automated Washing

Olivier Van Houtte

is product manager,

Life Sciences Washing

Systems, Steris, Olivier_

[email protected],

www.sterislifesciences.com.

Pharmaceutical Technology Europe JUNE 2015 49


Troubleshooting

All

fig

ure

s a

re c

ou

rte

sy o

f th

e a

uth

or.

spotting, increased detergent usage, and overall

poor cleaning performance may be encountered. It is

recommended that the washer supplier’s water quality

recommendations be followed. Water hardness must

also be considered. Hard water will often require a higher

concentration of chemicals. At a minimum, using mineral-

free water such as reverse osmosis, deionized, distilled, or

water-for-injection water in the final rinse phase will likely

improve the cleaning efficacy. Another option is to add a

formulated acid cleaning agent second wash following a

primary wash phase.

Basket loading. The positioning of load items and/or

overloading baskets can create problems in the cleaning

process. If items are positioned incorrectly, they may

receive inadequate coverage and as a result will not be fully

cleaned. It is imperative to follow the washer supplier’s

recommendations for the positioning of components

within the loading racks. For example, Figure 1 shows how

to use a clip on a spindle rack. Overloading the basket,

as shown in Figure 2, may also result in poor coverage

or inconsistent cleaning results. Overloading should be

avoided to ensure optimal cleaning.

Reference1. C.L. Wardrip, J.E. Artwohl, and B.T. Bennett, Contemp. Top.

Am. Assoc. Lab. Animal Sci. 33 (5) 66-68 (1994). PTE

Figure 1: A clip should be used on a spindle rack (a) to avoid improper positioning (b).

Figure 2: Overloading of baskets should be avoided.

Ad IndexCOMPANY PAGE

Angus .......................................................................................19

APV ...........................................................................................21

Brookfield Engineering ...........................................................37

Catalent Pharma Solutions ............................................... 27,52

COMBINO PHARM SL ..............................................................35

Emerson P.M (Systems) ............................................................2

ETQ Inc........................................................................................9

GE Healthcare Bio-Sciences AB.............................................17

Mueller GmbH ..........................................................................13

Nemera Services .......................................................................5

Panreac Quimica SA ...............................................................30

Patheon Pharmaceuticals ......................................................48

Rommelag AG ..........................................................................39

Sartorius Corporate Admin GmbH ........................................25

Shimadzu Europe ...............................................................33,51

Veltek Associates Inc ................................................................7

West Pharmaceutical Services .............................................. 11

CLASSIFIED DIRECTORY

To advertise in this section please contact:

Stephen Cleland Senior Sales Executive

Tel: +44 (0) 1244 629311 • Fax: +44 (0) 1244 659321

e-mail: [email protected] • www.pharmtech.com

CLASSIFIED WORKS

melaphonemelaphonesecure, hygienic and simple

visaudioMelaphone is designed for use in areas where hygiene and security are essential.

Melaphone speech panels are specifically

designed to allow sterile communication with a high

degree of vision and safety. There is no thru-air flow,

therefore, no transmission of germs, contaminants,

draughts or dust. The sytem is non-electrical nor

battery powered so requires the minimum

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Our double glqzing connecting system can be used

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Made in the UK

T : 00 44 (0)1359 233191E : [email protected]: www.melaphone.co.uk




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BROADEST DEVELOPMENT CAPABILITIESWith our complete range of dosage forms and comprehensive, integrated services, we create customized solutions that ensure superior results.

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MORE INHALATION EXPERIENCEFor over 20 years, our deep experience and effective program execution have accelerated inhalation drug development time to market.

new

Catalent Acquires Micron

Technologiesleader in particle

size engineering

inhalation

US + 1 888 SOLUTION (765 8846) EU 00800 8855 6178 [email protected] www.catalent.com

Discover more solutions with Catalent.

Breathe easier. Whatever your dosage form—pMDI, DPI, nasal, solution/suspension, or nebulizer—we are

the catalyst for your success. With our broad range of services and deep industry experience, we create

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DEVELOPMENT DELIVERY SUPPLY˝ 2

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