european

INDUSTRIAL
PHARMACY
features
4 LABORATORY SCALE SPRAY-DRYING OF
LACTOSE: A REVIEW
Lactose is widely used as an excipient for dry
powder lung delivery. This article reviews recently
published work in the lactose spray drying field using
laboratory scale spray dryers.
by Nina Schafroth and Marco Meuri

9 LABOUR LAW AND WHISTLEBLOWING:

ACCORDING TO EUROPEAN AND GERMAN
LEGISLATION
Whistleblowing continues to be highly contentious
especially when the employee informs the general
public via the press. The author, an attorney
specialising in labour and medical law, seeks to
clarify the situation.
by Martin Wesch

12 DEVELOPMENT OF A NOVEL INTRA-NASAL

SPRAY PRODUCT: A CASE HISTORY
The problems of formulation as well as the design of
the device are addressed by the authors in this
detailed case history.
by David P Elder, Andrew C Grant, Jim Godfrey, Anna Slater,
Gavin Bone and Gary Cannon

15 SWOT ANALYSIS USING GENERAL

MORPHOLOGICAL ANALYSIS: APPLICATION
TO THE SPECIALS SECTOR FOR NEW BUSINESS
DRIVERS
A major improvement of SWOT (Strengths,
Weaknesses, Opportunities and Threats) by a
problem structuring method is described in the
content of a start-up niche generic company.
by Nasir Hussain, Bruce Garvey and Thomas Ritchey

19 HOME HEALTHCARE: IT’S PEOPLE NOT

PRODUCTS THAT COUNT
The effect of a medical device on a patient’s life
should be one of the main considerations when
designing a device.
by Dan Formosa

regulars
3 EDITORIAL COMMENT
21 REGULATORY REVIEW
22 NEWS FROM THE EIPG
23 EVENTS

ISSUE 15 • DECEMBER 2012

www.industrialpharmacy.eu
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associate editors european
INDUSTRIAL
Belgium: Philippe Bollen PHARMACY
Issue 15 December 2012
Bulgaria: Valentina Belcheva ISSN 1759-202X

Czech Republic: Ales Franc EDITOR

Joe Ridge, MRPharmS
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european INDUSTRIAL PHARMACY

is the official publication of the European
Industrial Pharmacists Group (Groupement des Cover picture: Whistleblowing (see pages
Pharmaciens de l’Industrie en Europe) 9-11). Image: Fotolia
www.eipg.eu

2 european INDUSTRIAL PHARMACY December 2012 • Issue 15

editorial
Dear Colleagues
It is the end of another hectic year for the European
Industrial Pharmacists Group and what has been
another tumultuous year for the Pharmaceutical
Industry.
It was prophesied that 2012 in the Mayan calendar
would mark a catastrophic Global event (on
December 21st to be precise) – evidently the Mayans
were obviously predicting the catastrophic events
within the Pharma world.
We have seen CEOs come and go and profit
warnings combined with concerns about austerity
affecting pricing and innovation!
It is easy to be drawn into this gloom and doom
and yet, when I talk to many young Pharmacists there
is enormous interest in embarking on a career in
Industry and our duty as EIPG (which is written in our
statutes) is to guide and mentor such young talent.
My view and that of many of the EIPG member
states, is that the Pharmaceutical Industry still
provides an exciting career pathway for Pharmacists
but that the kind of roles and opportunities and
locations will be more global and varied.
In response to these changes, the EIPG has also
changed and as previously reported we have redrawn
our Statutes, which were constituted in 1966, to allow
the EIPG to reflect the various changes ongoing
within Europe and to allow greater participation of
non-EEC member states to join the EIPG.
I am proud to state that in 2012 we welcomed
Norway to the EIPG, Germany after many years of
complex negotiation was able to formalise its own
Association (well done Armin Hoffman for his dogged
persistence) and there have been enquiries from a
number of interested parties – the EIPG has never
been busier or healthier!
I have to acknowledge the sterling efforts and
support from the many individuals who have made
World Leader in GMP gap analyses,
seminars and individual GMP training
Hard hitting web-based GMP training in the
comfort and convenience of your office or
home (save on expensive and inconvenient
travel:
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• Effective Investigations and Corrective Actions
• Effective Quality Assurance Auditing
For full details and registration check our website at: www.globepharm.org/seminars.html/course
european INDUSTRIAL PHARMACY December 2012
my years as President an easy one to undertake. In
particular, I would like to formally thank the following
individuals who have worked with me throughout the
seven years:
Jane Nicholson – Executive Director
Claude Farrugia – Malta and Vice President
Piero Iamartino – Italy and Vice President
Jean-Pierre Paccioni – France and Vice President
Valerie Lacamoire – France and Vice President
whose enthusiasm and dedication has been
unfaltering despite balancing work pressures with the
challenges of supporting the EIPG often in their own
time and at weekends.
If I have my calculations correct, during my tenure
as President these individuals would have given up 28
days of their personal time to help the EIPG become
a force to be reckoned with and which represents the
individual Industrial Pharmacist and actually helps
more Pharmacists enter the Pharmaceutical Industry.
I would also like to acknowledge Joe Ridge and his
team for producing this splendid journal which I know
many Industrial Pharmacists and Pharmaceutical
Scientists read and enjoy. The feedback we receive is
very positive and we will continue to produce a
technical journal which puts pharmaceutical sciences
and regulatory good practice under one title.
With this, I would like to conclude this short
editorial and wish you a very exciting and prosperous
New Year!
Warmest regards
Gino
GMP and Quality System Consulting:
• ourselves
With over 200 clients in 27 countries, we pride
that every single one of our clients has
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Let us assist you. Speedily and cost effectively.
Contact us at: consulting@globepharm.org
• Issue 15 3
LABORATORY SCALE In contrast, the new Nano Spray
Dryer B-90 is based on a new spray
drying concept, as illustrated in
SPRAY-DRYING OF Figure 1(b). A comparison with the
traditional Mini Spray Dryer B-290 is
LACTOSE: A REVIEW given in Table 3.
The drying gas enters the
apparatus from the top where it is
by Nina Schafroth and Marco Meuri heated to the set inlet temperature,
flows then through the drying
Introduction chamber, and exits the spray dryer at
Spray drying is a commonly practiced method to prepare the bottom outlet. The gas is
inhalable powders and has been applied to a variety of additionally fine filtered before
substances, such as peptides, antibiotics, vaccines and leaving the instrument. The inlet
temperature and outlet temperature
biodegradable carrier particles1,2. The described delivery
are measured just after the heater
technology can be used for lung-specific applications to and before the fine filter. The liquid
treat cystic fibrosis, asthma, chronic pulmonary sample is fed to the spray nozzle via
infections, lung cancer or tuberculosis3,4. a peristaltic pump in a circulation
mode. The generation of droplets is
Nina Schafroth and Marco Meuri are Product Managers for spray drying at Buchi based on a piezoelectric driven
Labortechnik AG, Flawil, Switzerland. actuator, vibrating a thin, perforated,
Email: meuri.m@buchi.com stainless steel membrane in a small
www.buchi.com spray cap. The membrane (spray
mesh) features an array of precise,
Lactose is one of the most common dissolving an active ingredient micron-sized holes (4.0, 5.5 or 7.0µm).
excipients used for dry powder lung (drug, nanoparticles) and excipient The actuator is driven at around
delivery. The main properties of (lactose and others) in water at 60kHz, causing the membrane to
lactose are listed in Table 1. different solid concentrations. The vibrate, ejecting millions of precisely
Besides lactose, leucine, mannitol, resultant spray dried powder is sized droplets per second with a
glucose, trehalose and sucrose are separated by a cyclone and very narrow size distribution. These
other carriers which have been collected in a vessel. The exhaust extremely fine droplets are dried
studied over the past few years as gas is then extracted from the into solid particles and collected by
new inhaled drug delivery cyclone and filtered. electrostatic charging and
formulations5,6. These excipients are
approved by the Food and Drug Molecular formula C12H22O11
Administration (FDA) for pulmonary
delivery, and so, widely applied in Molar mass 342.3g/mol
aerosolisation. This is due to their Appearance White solid
non-toxic, readily degradable
properties after administration. Solubility in water 21.6g/100mL at 25°C
Lactose has the advantage of a Density 1.53g/cm3
low stickiness behaviour compared
to other sugars (see Table 2). Melting point 223°C
Moreover, its higher glass transition Glass transition point 101°C
temperature of Tg 101°C enables Table 1: Lactose properties. Lactose (or milk sugar) is a disaccharide
easy flowing powders. consisting of galactose and glucose fragments.
This article reviews recently
published scientific work in the field Sugars Hygro- Melting Water Stickiness
of lactose spray drying for inhalable scopicity point (°C) solubility at Tg (°C) (relative)
applications using laboratory scale (relative) 60°C (w%)
spray dryers.
Lactose + 223 35 101 +
The adjustable spray drying
process parameters are (see Maltose ++ 165 52 87 ++
Figure 1(a)):
l inlet and outlet temperature,
Sucrose +++ 186 71 62 +++
l sample feed rate, Glucose +++++ 146 72 31 +++++
l drying gas flow rate and
l spray gas flow Fructose ++++++ 105 89 5 ++++++
In the Mini Spray Dryer, mainly Table 2: Physical properties of sugars and stickiness behaviour (Tg: glass
aqueous solutions are prepared by transition temperature).

4 european INDUSTRIAL PHARMACY December 2012 • Issue 15

LABORATORY SCALE SPRAY-DRYING OF LACTOSE: A REVIEW continued

The mean particle appeared round and compact with a

sizes are generally in a smooth surface. By further dilution of
range of 1 to 5µm, the spray dried fluticasone and
which is generally salbutamol from 10% to 1% solution,
considered to be the Nano Spray Dryer B-90 appeared
effective for able to produce spherical submicron
pulmonary delivery. particles with smooth surface at high
Blank lactose carrier yields.
particles for blending
were in the 50-80µm Dry powder formulations
range. Moreover, spray Four main strategies are
drying is a one-step predominantly followed to formulate
process with narrow dry powders for inhalation
particle size applications based on lactose, as
distribution of illustrated below:
respirable dimensions
directly from liquid Group A: Small carrier-free drug
formulations9. particles
Spray drying allows Aerosol powders
control of particle ranging from 1
shape, morphology to 5µm are
and density considered the
Figure 1(a): Process diagram of the Mini Spray depending on the optimum size for
Dryer B-190, B-191 and B-290 models with process spray-drying deposition
parameters. conditions7. beyond the
Spherical particles increasingly
subsequent deflection to the can be prepared which provide a narrow airways into the alveoli.
collecting electrode. Finally the low contact area and homogeneous However, such small particles
resulting powder is collected using a particle size distribution resulting in often stick together, and are very
rubber spatula. a higher respirable fraction than cohesive with poor flow properties,
Overall, spray drying is a suitable mechanically micronised drugs. which makes physical handling of
alternative method for producing the particles difficult and lowers the
inhalable dry powders for pulmonary Particle morphology fine particle fraction.
applications. The main advantages SEM analysis shows that most of the Studies by Li et al.9,10
compared to freeze dried and jet spray dried lactose micro-particles demonstrated that the dose
milled products are summarised in were spherical in shape. The fine emission and dispersibility of spray
Table 4 on page 7. microparticle agglomerates dried lactose particles were
Today, the market for inhalable dry
powders relies on freeze dried and Nano Spray Dryer B-90 Mini Spray Dryer B-290
jet milled micronised drugs6. Main benefit for small quantities, finest for traditional spray drying,
However, comparable size particles, highest established process
distributions are achieved of the yields
same substances with spray dried or
jet milled spray dried powders, but Max. inlet temperature 120°C 220°C
particle morphology can more easily Water evaporation max. 0.2kg/h 1.0kg/h, higher for solvents
be influenced by spray drying than Nozzle type piezoelectric driven two-fluid nozzle
by jet milling7. vibrating mesh
Compared to freeze drying, spray Particle size 300nm – 5µm 2 – 25µm
drying generates highly dispersible
powders for inhalation without the Particle separation electrostatic particle collector cyclone
use of carrier particles. The jet Typical yield up to 90% typically around 60%
milling process leads to small, flat, Min. sample volume 1mL 30mL
crystalline particles and stronger Max. sample viscosity 10cps (diluted samples) 300cps (viscous samples
cohesive forces with poor flow and juices possible)
properties.
Compared to the crystalline Scale-up limited by spray head and possible to scale-up to kg-
nature of jet milled lactose, the electrical particle collector and tons-scale
structure of spray dried lactose is Table 3: Comparison of main features and benefits between Nano Spray
amorphous8. Dryer B-90 and Mini Spray Dryer B-290

european INDUSTRIAL PHARMACY December 2012 • Issue 15 5

LABORATORY SCALE SPRAY-DRYING OF LACTOSE: A REVIEW
considerably enhanced in the fluticasone propionate were spray
presence of amino acids, specifically dried in 10% lactose solution and
leucine, phenylalanine and arginine. the resulting size distributions were
Incorporation of NaCl and its shown to be in the 1-3µm range. At
relative proportion was also efficient further diluted concentrations, the
to control the aerosol properties of Nano Spray Dryer B-90 appeared to
spray dried rhDNase powders11. The provide very satisfactory results for
presence of NaCl changed the the formulation of submicron
morphology and crystallinity of the particles from small sample
co-spray dried powders, and this amounts. This novel spray drying
was paralleled by improvement in technology offers promising
the fine particle fraction of rhDNase. perspectives for new pharmaceutical
In particular, in blends with about applications using spray drying.
50µm lactose carrier particles the
rhDNase particles adhered Group B:
apparently in the form of a Small drug
monolayer to the carrier. and larger
Ely et al.3 produced inhalable carrier
effervescent powders and used a particles
mixture of acids such as citric acid The most
and carbonates. Different common
ingredients such as ethanol, approach to
polysorbate 80, L-leucine and PEG overcome
6000 were added to the basic the cohesiveness of small particles
formulation to improve the particle is the use of carrier particles
size and to achieve an appropriate markedly larger than the drug
mass medium particle diameter. particles7,11,12. The aggregation
The experiments with the Nano problem is solved by particle size
Spray Dryer B-90 illustrate the enlargement, which involves an
promising potentials with high additional blending step of the
fabrication yields and very narrow small drug particles (active
size distributions. ingredients, such as budesonide
The asthma drugs, salbutamol and and formoterol fumarate dehydrate)
with large lactose
carrier particles to
improve their flow
through the inhaler2.
Lactose is the most
commonly used carrier
for Dry Powder Inhaler
(DPI) formulations,
where it is usually
desired to have a size
of about 50µm to
80µm for this
purpose13. During
inhalation, the smaller
drug particles
separate from the
carrier particles and
are deposited in the
alveoli.
Trehalose and
mannitol are also
known to improve
protein stability,
although the use of
Figure 1(b): Process diagram of the new Nano mannitol in this regard
Spray Dryer B-90 with process parameters. is limited due to its
6 european INDUSTRIAL PHARMACY December 2012
continued
susceptibility towards crystallisation.
While the spray dried trehalose was
amorphous, spray dried mannitol
recrystallised5.
For nasal administration, an
agglomeration step is successfully
applied to transform primary spray
dried micro-particles into spherical
and flowable agglomerates, as
shown by Russo et al.14 for
morphine particles.
Group C: Large
porous drug
particles
A breakthrough in
inhaled dry
powder aerosols
research was
made with the
development of large porous
particles (>5µm) with low mass
density (<0.4g/cm3) by Edwards et
al.15. It has been shown that larger
particles aggregate less and
disaggregate more easily. These
large porous particles are
specifically designed to serve as an
alternative to the conventional small
non-porous drug particles (Group
A). They can be manufactured via
spray drying because of process
simplicity, cost effectiveness, and
scale-up capability.
By virtue of their larger size, the
porous particles have better
flowability and are thus capable of
evading the phagocytic clearance
mechanism in the lungs, which leads
to an improved therapeutic efficacy
of the inhaled drug.
Group D: Encapsulated nano-
particle drugs in carrier particles
Nanoparticulate
drugs as
therapeutic
carriers has
become the
subject of very
active research8. Nanomedicine is an
emerging field in the bio-medical
sciences3. Nanoparticles have also
been proposed for pulmonary
administration to utilise their
advantages in drug delivery to the
lungs4. However, one issue is that
their small size limits their lung
deposition. Aerosolised
• Issue 15
LABORATORY SCALE SPRAY-DRYING OF LACTOSE: A REVIEW continued

most publications as around 48%

1. Highly dispersible and spherical particles in a range of 1 to 5µm with
narrow particle size distribution.
2. Control of particle shape, morphology and density depending on
spray drying conditions.
3. One-step process directly from liquid to dry formulations.
4. Process simplicity, cost effectiveness and scale-up capability.
Table 4: Advantages of spray drying compared to freeze dried and jet milled
products to produce inhalable dry powder for pulmonary applications
nanoparticles have only very limited
sedimentation, inertial impaction or
diffusion, which causes them to be
predominantly exhaled from the
lungs after inhalation.
Research focus is therefore on the
incorporation of nanoparticles into
carrier particles to produce the
appropriate size for pulmonary drug
delivery8. For example, Sham et al.4
incorporated gelatin nanoparticles
into lactose powders by spray
drying. The gelatin nanoparticles
were evenly distributed throughout
thelactose carrier particles. After
spray drying the nanoparticles
remained in the nano-range size.
This promising technique was also
used to incorporate biodegradable
polymer and protein-based
nanoparticles into lactose carrier
particles.
Spray dried silica nanoparticles in
lactose was studied by Hadinoto et
al.8 and Kho and Hadinoto5. Here,
the degree of hollowness decreased
as the concentration of nanoparticles
increased. Spray drying of lactose in
the absence of nanoparticles yielded
large solid spherical particles,
whereas the presence of
nanoparticles led to an apparent
decrease in the molecular diffusivity
of the lactose solutes and produced
hollow particles.
Such large, hollow nanoparticulate
aggregates may serve as new
micron-sized carriers of
nanoparticulate drugs for delivery by
dry powder inhalers.
Moreover, Kho and Hadinoto5
found that a multiple-excipient
formulation of leucine and lactose
at a 1:6 concentration ratio was
capable of producing optimal
results in terms of both the
nanoaggregate morphology and
aqueous re-dispersibility. The high
aqueous solubility of lactose
facilitated the effective re-
dispersion of the nano-aggregates,
whereas the presence of
hydrophobic leucine stabilised the
nano-aggregates by reducing their
cohesiveness.
Lactose structure after spray
drying
Control of the structural state of
spray dried pharmaceuticals is of
major importance. Spray drying is
often used to produce amorphous
composites which are generally
attributed to the rapid drying
process leaving very short time for
evaporation and formation of the
solid phase16. Lactose is typically
100% amorphous after spray drying
because of the short residence time
in the spray dryer12 and its high
glass transition temperature17 (see
Table 2).
A drawback of the amorphous
state is that this metastable form
will, if not stabilised, spontaneously
crystallise over time, which may
result in agglomeration and caking
of the primary particles so that the
product becomes non-inhalable.
Major factors affecting the
physical instability of amorphous
lactose are the physico-chemical
properties of the materials; in
particular the glass transition
temperature of the applied
materials and the crystallisation
temperature, as well as the spray
drying processing variables such as
the drying temperature and the
relative humidity of the drying air.
The absorbed water has a
plasticising effect on the lactose.
The critical relative humidity at
which the glass transition
temperature falls below room
temperature (25°C) is quoted in
relative humidity12.
Residual moisture contents of
about 2% to 11% are typically
measured for spray dried powders
containing lactose18,19.
Co-spray drying of lactose and
polyethylene glycol (PEG) was
shown to promote crystallisation of
lactose12,16,20. Crystallisation was
favoured by a low molecular weight
and a high concentration of PEG16.
The presence of PEG 6000 changed
the surface texture of the carrier
particles from a smooth surface to a
more aspirated surface20. An
increase in lactose content in the
feed solution resulted in a decrease
in amorphous lactose percentage in
the spray dried products12.
Islam and Langrish20 studied the
effect of NaCl and KCl salts on
lactose crystallisation and obtained
the most crystalline product at a
lactose to NaCl ratio of 5 to 2 (w/w).
The effect of varying the inlet air
temperature on the degree of
crystallinity for spray dried lactose
powders was studied by Chiou et
al.21 and Islam et al.17.
A higher degree of crystallinity
(from about 55% to 76%) was
observed in spray dried lactose
when an inlet gas temperature of
210°C was used, compared with an
inlet gas temperature of 134°C21.
Moreover, an insulated spray
chamber was beneficial to reduce
heat losses due to radiation17.
Langrish et al.18 investigated spray
drying of skimmed and whole milk
in the MiniSpray Dryer B-290. Yield
values of up to 82.7% (skimmed
milk) and 18.6% (whole milk) were
found. The lower yields were
attributed to wall deposition due to
the sticky nature of milk types with
higher levels of fats and sugars, such
as whole milk and lactose free
skimmed milk.
Conclusions
Inhalable applications
l Spray drying is able to produce
stable, efficient and inhalable dry
lactose powder systems for
respiratory delivery with adequate
particle size and shape for deep
lung deposition 3,4,6,7.

european INDUSTRIAL PHARMACY December 2012 • Issue 15 7

LABORATORY SCALE SPRAY-DRYING OF LACTOSE: A REVIEW
Spray drying versus jet milling
l Spray drying and jet milling
showed insignificant differences in
fine lactose particle size of the
same formulations13.
l Spray dried particles showed
higher dispersibility compared to
jet milled particles due to
spherical shape and smaller
surface contact area7.
l The dissolution and inhalation
behaviour of spray dried powder is
even more advantageous than that
of mechanically micronised
powder. Spray dried particles free
themselves from the large lactose
carrier particles as easily as
mechanically micronised particles7.
Aerosol properties and
dispersibility
l The aerosol properties and
dispersibilty of spray dried
powders can be enhanced by
incorporation of suitable
excipients, such as NaCl salt11,19 or
amino acids5,9,10 before spray
drying, allowing the development
of stable and viable formulations
for pulmonary inhalation.
Amorphous/crystalline structure
l The rapid solidification in spray
drying causes lactose in
suspension to become
amorphous12. Various polymorphic
proportions can be manufactured
by selection of the appropriate
feed concentrations.
l Spray drying process conditions
may be utilised to alter the final
spray dried lactose product, where
the inlet gas temperature has a
significant impact on the
crystallinity17,21.
l The presence of polyethylene
glycol promotes crystallisation of
lactose when the two components
are co-spray dried12,16,20.
l Crystallisation is favoured by a low
molecular weight and a high
concentration of PEG16.
Nanoparticles
l Incorporation of nanoparticles into
respirable carrier particles can be
a straightforward process when
formulating via spray drying4.
8 european INDUSTRIAL PHARMACY December 2012
Spray dried nanoparticle
aggregates are capable of serving
as micrometer-sized carriers of
nanoparticulate drugs. This
facilitates the nano-particle
delivery to the lung for potential
inhaled drug delivery applications
in Dry Power Inhalers5,8.
l The Nano Spray Dryer B-90
provides a novel spray drying
technique in laboratory scale to
prepare submicron particles for
pulmonary delivery dry powder
formulations.
Acknowledgments
BÜCHI Labortechnik AG thanks all
scientists listed in the references for
the research carried out on BUCHI
spray dryers.
References
1 Arpagaus C, Schafroth N. Laboratory
scale spray drying of
biodegradablepolymers. Respiratory Drug
Delivery 2009: 269-274.
2 Arpagaus C, Meuri M. Laboratory scale
spray drying of inhalable particles: a
review. Respiratory Drug Delivery 2010:
469-476.
3 95:(12):2553-2561.
Ely L, Roa W, Finlay WH, Löbenberg R.
Effervescent dry powder for respiratory
drug delivery. European Journal of
Pharmaceutics and Biopharma-ceutics
2007;65:346-353.
4 Sham JO-H, Zhan Y, Finlay WH, et al.
Formulation and characterization of spray-
dried powders containing nanoparticles
for aerosol delivery to the lung.
International Journal of Pharmaceutics
2004;269:457-467.
5 Kho K, Hadinoto K. Effects of excipient
formulation on the morphology and
aqueous re-dispersibility of dry-powder
silica nanoaggregates. Colloids and
Surfaces A: Physicochem. Eng. Aspects
2010;359:71-81.
6 Seville PC, Kellaway IW, Birchall J C.
Preparation of dry powder dispersions for
non-viral gene delivery by freeze-drying
and spray drying. Journal of Gene 2002;
4:428-437.
7 Vidgrén MT, Vidgrén PA, Paronen TP.
Comparison of physical and inhalation
properties of spray dried and mechanically
micronized disodium cromoglycate.
International Journal of Pharmaceutics
1987;35:139-144.
8 Hadinoto K, Phanapavudhikul P, Kewu Z,
Tan RBH. Novel formulation of large
hollow nanoparticles aggregates as
potential carriers in inhaled delivery of
nanoparticulate drugs”, Industrial &
Engineering Chemistry Research 2006;
45:3697-3706.
9 Weiler C, Egen M, Trunk, Langguth P.
Dispersibility of jet milled vs. spray dried
continued
powders. Respiratory Drug Delivery. 2008:
571-575.
10 Li -Y, Neill H, Innocent R, et al. Enhanced
dispersibility and deposition of spray-
dried powders for pulmonary gene
therapy. Journal of Drug Targeting
2003;11(7):425-432.
11 Li-HY, Seville PC, Williamson IJ, Birchall
JC. The use of amino acids to enhance
the aerosolisation of spray-dried powders
for pulmonary gene therapy”, Journal of
Gene Medicine 2005;7:343-353.
12 Najafabadi AR, Asgharian , Tajerzadeh, H,
et al. The effects of fine lactose as a third
component on aerosolization of
cefotaxime sodium from dry powder
formulations. DARU Journal of Faculty of
Pharmacy Tehran University of Medical
Sciences 2006;14(3):150-163.
13 Chan H-K, Clark, A, Gonda I, et al. Spray
dried powders and powder blends of
recombinant human deoxyribonuclease
(rhDNase) for aerosol delivery.
Pharmaceutical Research 1997;14(4):431-
437.
14
Chidavaenz OC, Buckton G, Koosha F,
Pathak R. The use of thermal techniques
to assess the impact of feed concentration
on the amorphous content and
polymorphic forms present in spray dried
lactose. International Journal of
Pharmaceutics 1997;159: 67-74.
15 Russo P, Sacchetti C, Pasquali I, et al.
Primary microparticles and agglomerates
of morphine for nasal insufflation. Journal
of Pharmaceutical Sciences 2006;
16 Edwards DA, Hanes J, Caponetti G, et al.
Large porous particles for pulmonary drug
delivery. Science 1997;276:1868-1871.
17 Mosen K, Backstrom K, Thalberg K, et al.
The apparent plasticizing effect of
polyethylene glycol (PEG) on the
crystallinity of spray dried lactose/PEG
composites. European Journal of
Pharmaceutics and Biopharmaceutics
2006;64:206-21.
18 Islam MIU, Langrish TAG. An investigation
into lactose crystallization under high
temperature conditions during spray
drying. Food Research International
2010;43:46–56.
19 Langrish TAG, Marquez N, Kota K. An
investigation and quantitative assessment
of particle shape in milk powders from a
laboratory-scale spray dryer. Drying
Technology 2006;24(12):1619-1630.
20 Islam MIU, Langrish TAG. The effect of the
salt content on the crystallization
behaviour and sorption fingerprints of
spray-dried lactose”, Food and
Bioproducts Processing 2008;86:304-311.
21 Corrigan O-D, Healy A-M, Corrigan O-I.
The effect of spray drying solutions of
polyethylene glycol (PEG) and
lactose/PEG on their physicochemical
properties, International Journal of
Pharmaceutics 2002;235:193-205.
22 Chiou D, Langrish TAG, Braham R. The
effect of temperature on the crystallinity
of lactose powders produced by spray
drying. Journal of Food Engineering 2008;
86(2): 288–293.
• Issue 15
LABOUR LAW AND Chief Executive, about what was
happening, but to no avail.4
Following her dismissal because
WHISTLEBLOWING of this action in 2003, she
informed the FDA.
According to European and German c) The most famous whistleblower
in the world, “WikiLeaks” fell
legislation silent at the end of 2010. The
home pages were removed from
by Martin Wesch the net. Numerous secret papers
from ambassadors and the US
military about the wars in Iraq

A nyone who, in the public interest, discovers

shortcomings in his/her employer, particularly in the
state sector, earns public recognition. Unusual
and Afghanistan had previously
been published.5

Freedom of speech in
termination of office without notice is a particular case in accordance with the ECHR
point. Complaints against employers are viewed as a) According to the European Court
significant grounds since these are consistent with failure of Human Rights (ECHR), those
on the part of the employer to comply with the Member States coming under its
jurisdiction are obliged to protect
employment contract until the standard period of notice the right to freedom of speech
has elapsed. This article seeks to clarify whether and to (pursuant to Article 10 of the
what extent the aforementioned behaviour adopted by European Convention on Human
employers is legally permissible and should remain Rights) in dealings between
private persons.6 In the case
devoid of sanctions in accordance with labour law.
where an employee detected
shortcomings in the treatment
Dr. Martin Wesch is an Attorney specialising in Labour and Medical Law and care of the elderly and
email: STR-law@wesch-buchenroth.com subsequently filed a complaint
against the employer, the ECHR
viewed this as a violation of the
Issues the USA are entirely different. A right to freedom of expression
a) The media draws widespread subsidiary of GlaxoSmithKline through the German courts. With
public attention to the fact that (GSK) in Puerto Rico committed the exception in the first instance
there are shortcomings in the itself to criminal proceedings in of the Berlin Employment
treatment and care of the 2010 and had to pay 750 million Tribunal, the courts considered
elderly. Those affected are US dollars in fines and damages the employee’s termination of
looked after inadequately or not for the manufacture and sale of contract without notice to be a
at all. This is often due to staff certain adulterated drugs.2 This legitimate outcome.
shortages fuelled by an refers to the drugs Kytril, b) The ECHR maintains that the
overwhelming desire to make Bactroban, Paxil CR and employee should initially have
profits. In the food industry, Avandamet, which were reported the information to
cattle with BSE or rotten meat produced between 2001 and his/her line manager based on a
are used in food production. 2005. The whistleblower, the loyalty or confidentiality
Allegations of bribery are Quality Control Manager, was obligation.7 Only if this approach
sometimes lodged against major supposed to receive almost 96 proves impossible or fruitless
companies. However, violation of million US dollars of that.3 This should the employee bring this
the employment law can also was based on the False Claims case into the public domain as a
impact upon employers Act of 1863, which allowed last resort. When weighing the
themselves, e.g. if an employee private citizens to take civil action extent of interest, it is important
alleges that the Managing on behalf of the United States to establish whether there would
Director committed a traffic and participate in a productive indeed be public interest in such
violation during a joint business outcome, comparative FDA press a case and whether such interest
trip in order to get the latter’s report dated 26.10.2010, the law would be well-founded. Anyone
driving licence revoked.1 was accepted in civil law in order wishing to pass on the
b) Whereas in Europe such cases to put a stop to the action of information must basically check
give rise to disputes over the fradulent army suppliers. For 10 whether the details are accurate
employer’s right to terminate the months she had repeatedly and reliable. Furthermore, the
whistleblower’s contract without attempted to inform her line damages possibly sustained by
notice, the legal consequences in managers, right up to the GSK the employer should be taken

european INDUSTRIAL PHARMACY December 2012 • Issue 15 9

LABOUR LAW AND WHISTLEBLOWING
into account together with the
reasons for providing the
information and the type of
sanction. A complaint against
shortcomings in the workplace
can be justified when there are
no grounds to reasonably expect
that in-house grievances will lead
to an investigation and
corrective action. Evidence must
be substantiated and should not
be knowingly or deliberately
falsified. Further to inconclusive
in-house grievances, the
employee in the case dealt with
by the ECHR could assume that
a complaint would be the last
resort in any attempt to improve
the care situation. Public interest
in shortcomings in the care of
the elderly in state-run nursing
homes attracts so much
attention that it actually
outweighs the company’s
interest in protecting its good
reputation in terms of business
connections and business
interests.
c) Violation of Article 10 of the
European Convention on Human
Rights by the German courts did
not lead to the reinstatement of
the care assistant. Pursuant to
Article 41 of the aforesaid
Convention, Germany was
instructed to pay legal
compensation to the person who
filed the complaint. In this
particular case, this amounted to
€10,000.00 to compensate for
non-pecuniary damages and
€5,000.00 in costs and expenses.
Germany had to pay the
damages within three months but
the person who lodged the
complaint lost her job.
The consequences of
jurisdiction in Germany
a) National jurisdiction has already
been adjusted in line with ECHR
decisions. In the case of so-called
whistle blowing, the German
Bundesarbeitsgericht (BAG –
Federal Labour Court) states that,
on constitutional grounds, an
employee must not be
disadvantaged in accordance
with civil or labour law if he/she is
10
exercising civil rights within the
scope of preliminary penal or
regulatory proceedings providing
that no untruths are knowingly
stated and information is not
deliberately falsified.8 The
constitutional rights of the
employee (in accordance with
Article 2 para. 1 of the said
Constitution and the
fundamental right to general
freedom of action, in conjunction
with the due process of law)
resonate with the employer’s
obligation to provide protection
and consideration (in accordance
with § 241 para. 2 BGB). In filing
a complaint with the Publication
Prosecution Department and
contacting the Bundesanstalt für
Finanzdienstleistungsaufsicht
(BaFin – Federal Financial
Supervisory Authority), the
employee has adopted
approaches that are approved
and permitted by the legal
system. He/she should highlight
the proceedings which, in his/her
opinion, constitute grounds for
complaint, to the employer in
conjunction with organisational
involvement and allow them to
be investigated by competent
state bodies.9 Civil rights have
been exercised by sending the
employer’s documentation to
these authorities.
b) The case of the announcement
against the managing director
who allegedly committed a traffic
violation was viewed differently.
In this case, the employee
wanted to have the managing
director’s driving licence revoked.
This was viewed by the BAG as
tantamount to destroying any
basis for trust between the
parties to the contract.
Extraordinary termination of
contract without notice was
therefore considered justified.10
c) An employee who is responsible
for the safety of operating
devices, e.g. in a nuclear research
plant, must raise safety
objections to the competent
state authorities in an
appropriate format.11 The
employee’s termination of
european INDUSTRIAL PHARMACY December 2012
continued
contract on this basis was
ineffective.
d) In Germany, the threat of a
complaint against the employer
is sometimes viewed as sufficient
grounds for termination of
contract.12 The employee is not
even covered if he asks a third
party to deliver the threat on
his/her behalf. If the employee
has initiated or at least approved
of the threat, termination of
contract without notice may be
justified.13
International legislation and
endeavours to this effect
a) Ways of improving protection for
whistleblowers is under
discussion in many countries.
One Canadian woman
provocatively suggested that it
was a case “of breaking the
silence of the lambs”14. In Great
Britain15, Australia16, recently in
Ireland17 and even in Romania18
there are certain laws to protect
whistleblowers when they are
employees. Whistleblower
protection in Belgium19, the
Netherlands20, France21 and
Germany22 only falls under
general bans on discrimination.
b) Germany is still wrestling with
appropriate protection for
whistleblowers. The Federal
Government sees no need for
whistleblower legislation.23 A ban
on disciplinary measures is
already in force, according to
which an employer cannot
discriminate against an employee
because the latter is exercising
his/her rights in an appropriate
manner (§ 612 a BGB).
Recommended behaviour
Employer
The employer can facilitate
anonymous in-house reporting by
the employee. A secure site must
be provided where the employee
can voice his concerns without fear
of sanctions. Companies often
appoint an “Ombudsman” for this
purpose. The latter must be bound
by secrecy. Anonymous reports can
also be received by ombudsmen. In
this way, the employer is made
• Issue 15
LABOUR LAW AND WHISTLEBLOWING
aware of in-house shortcomings. It
is easier for employees to make
themselves known to the employer.
They do not have to reveal their
personal data. This can also easily
lead to unjustified reports against
line-managers or unpopular
colleagues (“black-listing”). The
ombudsman will have to weigh up
whether the charges are justified
and directed against individual
people. This will depend on the
nature, severity and frequency of
the violation as well as the level of
accuracy in terms of presenting the
evidence. The ombudsman will then
decide which procedures the
employer should introduce in order
to clarify the situation and initiate
corrective measures.
The introduction of an
ombudsman, “ethics hotline” or
“whistle blowing systems” in
Germany is not devoid of problems
from a data protection perspective.
Personal data must only be used by
the employer when needed to
justify, implement or terminate a
working process. This is sometimes
permitted only when there is a
binding obligation in Germany or
the EU to record and monitor data
and not when it concerns
compliance with an in-house
company policy based on legal
proceedings in other countries. The
extent to which personal data
should be collated and processed
must be carefully weighed by the
ombudsman and the in-house
complaints office. Necessity will be
based on the extent, severity and
frequency of the violation and the
accuracy of the presentation.
Employees
In any case, whistleblowers are
advised initially by the employer
and in-house to seek corrective
measures in an appropriate manner
and without threats. Whether
shortcomings are pointed out to the
employer anonymously or with
disclosure of identity is irrelevant. It
is, however, crucial for the
shortcoming to be reported to the
employer via relevant channels. The
european INDUSTRIAL PHARMACY December 2012
shortcoming must also be
presented in sufficient detail with
accompanying evidence where
possible (especially witnesses,
documentation or visual inspection
of locations or objects). Employees
must have an opportunity to
consider individual shortcomings.
General complaints that have no
sound basis and which may lead to
violation need not be pursued by
the employer. However, if the
employer does not take action
despite substantial evidence and in
situations where the employee
cannot reasonably expect his/her in-
house complaint to generate an
inspection and corrective measures,
a complaint against shortcomings in
the workplace is justified.
It is open to debate as to whether
the employee is also entitled to
inform the general public via the
press. The inevitable damage to the
employer’s reputation is quite
simply justified on the basis of
freedom of speech pursuant to
Article 10 of the European
Convention). Such considerable
impacts on the rights of the
employee are weighed in terms of
public interest only in the severest
of shortcomings in the workplace
where human life and health are at
risk or the environment is under
threat. This does not, however,
apply when the employee wishes
merely to pursue personal gain or
desires revenge. Employees should
therefore exercise particular caution
when reporting to the press. Public
interest in the information will
occasionally oppose termination of
the employee’s contract but only in
the severest of cases.
References
1
Comparable Bundesarbeitsgericht (BAG)
dated 18.12.1980, Practice in accordance
with Labour Law, BAG (Federal Labour
Law) Reference Work No. 4 to § 174 BGB
(German Civil Code).
2 Food and Drug Administration (FDA),
Office of Criminal Investigations, Press
report dated 26.10.2010, www.fda.gov.
3 http://en.wikipedia.org/wiki/Whistleblower.
4 Simon Goodley in “The Guardian”, 28
Oct. 2010, www.guardian.co.uk.
• Issue 15
continued
5 Available at:
www.canadianlawsite.ca/whistle-
blower.htm
6 ECHR, judgement dated 21.07.2011 –
28274/08, Neue Zeitschrift für
Arbeitsrecht 2011, 1269.
7 See in the following: ECHR, judgement
dated 21.07.2011 – 28274/08, Principles.
8 BAG, Judgement dated 14.12.2011 – 10
AZR 283/10 Text reference 23.
9 BAG, at the specified location.
10 BAG dated 18.12.1980, Labour Law-
related practice No. 4 to § 174 BGB.
11 BAG dated 14.12.1972, Labour Law-
related Practice No. 8 to § 1
Kündigungsschutzgesetz (Legislation
providing Protection against Termination
of Contract) Verhaltensbedingte
Kündigung (Behaviour-related
Termination of Contract).
12 Mueller-Gloege im Erfurter Kommentar
zum Arbeitsrecht (Discussions on Labour
Law),11th Edition2011, Kennzahl 230,
§ 626 BGB Marginal Number 64.
13 Essen Court of Employment dated
15.05.2009, Neue Zeitschrift für
Arbeitsrecht- Rechtssprechungs-Report
2010, 75.
14 Rosella Melanson in the New Brunswick
Telegraph Journal May 2001. Available at:
www.canadianlawsite.ca/whistle-
blower.htm#f; little store is set by
protecting whistleblowers in this article.
Available at:
http://en.wikipedia.org/wiki/Whistleblower.
15 Public Interest Disclosure Act 1998
(PIDA). Available at: www.cipd.co.uk/hr-
resources/factsheets/whistleblowing.aspx.
16 Whistlesblowers’ Protection Act 2001.
Available at:
www.austlii.edu.au/au/legis/vic/consol_act/
wpa2001322/ (accessed 23 October 2011).
17 Whistleblower Protection Law since
January 2012. Available at:
http://en.wikipedia.org/wiki/Whistleblower.
18 Act on the Protection of Whistleblowers
(Law No. 571/ 2004, Priority on other
national laws). Available at:
www.europarl.europa.eu/document/activit
ies/cont/201105/20110524ATT20164/201
10524ATT20164EN.pdf.
19 Klokkenluidersdecreet in the Vlaamse
Ombudsdienst, see footnote No. 18.
20 Civil Servants Act, see footnote No. 18.
21 Loi n° 2007- 1598 relative à la lutte contre
la corruption (French law No. 2007-1598
relating to the fight against corruption),
see footnote No. 18.
22 Law on the Status of Civil servants, see
footnote No. 18.
23 Publication in the Frankfurter Allgemein
Zeitung (FAZ Online) dated 31.05.2012:
“Ausplaudern erwünscht“
(Whistleblowers wanted).
11
DEVELOPMENT OF A delivery properties as well as
generating leachable impurities.
For multi-use products the
NOVEL INTRA-NASAL efficacy of the preservative system
needs to be evaluated during the
SPRAY PRODUCT – A CASE product’s in-use period as well as
over its entire shelf-life.

HISTORY Container-closure systems

The design of the container-closure
system can have significant impact
by David P Elder, Andrew C Grant, Jim Godfrey, Anna Slater, on the dosing performance of the
Gavin Bone and Gary Cannon drug product. The design attributes
of the device need to address the
potential for operator-dependent
I ntra-nasal spray products contain active ingredient(s),
which are dissolved/suspended in vehicles comprising
a variety of functional excipients, such as isotonicity
actuation, particularly if
paediatric/geriatric use is being
considered. Both the metering and
agents, preservatives, suspending agents, viscosity spray producing attributes (e.g.
modifying agents (bio-adhesives), buffering agents and orifice, nozzle, etc) components are
used to generate reproducible
emulsifiers. These products are presented in non-
drug delivery. These constituents
pressurised dispensers that deliver metered dose are constructed from many plastic
sprays of the active ingredient, as either multi-use or sub-components that need to be
single dose products1. The container-closure system is precisely controlled both in terms
comprised of the container, closure, metering pump, of dimensional attributes
and any secondary packaging; the formulation and (impacting on manufacturability
and operational performance) as
container-closure system comprise the drug product. well as composition (impacting on
leachable profile).
David P Elder and colleagues are in the R&D Division of GSK in Ware, This review will focus on the
Hertfordshire, UK. Email: david.p.elder@gsk.com development of an intra-nasal spray
product, which utilised a novel side-
actuated device that was developed
Intra-nasal products deliver a spray therapeutic effect when droplets in parallel with the formulation.
of droplets into the nasal cavity for are deposited between the nasal
either local (topical), or systemic valves in the posterior two-thirds of Design attributes of an intra-nasal
action for direct delivery to the the nasal cavity3. spray product
brain. There is a relatively short Intra-nasal spray products have A Quality by Design (QbD) risk-
nasal residence time (up to 20 to 30 some unique aspects that can based approach was applied to the
minutes) before mucociliary impact on both stability and development of an intra-nasal
clearance mechanisms will drain the performance. These aspects spray4. The drug product should
administered dose down the include: the physicochemical nature provide a consistent dose to the
nasopharyngeal tract2. of the formulation composition may patient with respect to: (i) amount
The pump design influences the be critical in describing both the of drug delivered, (ii) DSD (Droplet
actuation force, pump valve design, stability (chemical, physical and Size Distribution) of the nasal spray,
metering chamber design, length microbiological aspects) and and (iii) amount of small droplets
of actuator and nozzle orifice performance characteristics of drug (<10µm) which should be
design. The FDA guidance states products. These physicochemical minimised (this reduces potential
that with respect to droplet size properties together with the for inhalation into lungs).
and particle size distribution, that potential for agglomeration, Structured-risk based methods
this ‘is an important property sedimentation or flocculation on were applied, which are aligned
influencing the nasal deposition of storage can be crucial to the with ICH Q95. The drug product was
aerosols and sprays’. This is performance of the drug product, designed to meet appropriate
because droplets less than 10µm influencing suspendability and quality standards in routine
can potentially enter the lungs; particle characteristics as well as manufacture at commercial scale.
whereas, excessively large droplets device delivery performance. Qualitative studies using external
will be deposited at the front of the Similarly, the potential for consultants were used to identify
nostril and ‘run-off’ from the nasal interaction of the formulation with patient/physician’s dissatisfaction
cavity. The majority of nasal internal contact surfaces, particularly with currently marketed nasal sprays
medicines achieve maximum elastomeric materials, can influence (see Table 1).

12 european INDUSTRIAL PHARMACY December 2012 • Issue 15

DEVELOPMENT OF A NOVEL INTRA-NASAL SPRAY PRODUCT
Risk analysis
Container closure system
The intra-nasal product was
developed by first-intents to mitigate
the following potential risks
associated with the delivery system:
– Potential instability of the
formulation due to inadequate
protection during shelf-life
(chemical, physical and
microbiological effects)
– Potential change in formulation
composition and performance
arising from moisture loss/uptake
– Potential incompatibility of
formulation and product contact
materials (novel degradation
and/or leachable/extractables )
– Potential variability of in vitro/in
vivo performance as a result in
variation of key device component
attributes (ex-device spray
characteristics)
– Potential variability of in vitro/in
vivo performance due to inability
of device to maintain prime
between doses (ex-device spray
weight characteristics)
Container
Type I glass was selected to minimise
the potential for leachables and
adsorption of the drug product and
to minimise moisture loss/uptake or
adsorption of other components.
Amber glass was selected to provide
protection from ambient light as
there was a slight increase in
impurities observed after exposure of
unprotected drug substance to high
intensity light. The bottle was shaped
to minimise the overall size of the
device with a nominal fill volume
consistent with the target fill weight
for the commercial product.
Figure 1. Side actuated device (left) facilitates carer administration,
compared to top actuated devices (right)
european INDUSTRIAL PHARMACY December 2012
Table 1. Patient/carer/physician’s preferences for new intra-nasal
steroid spray
Patient/carer/physician’s preferences
1. Reduced post-nasal drip
2. Scent-free
3. Removal/reduction of additives that
might cause nasal stinging/burning
4. Device is easy to use correctly and is
suitable for use by paediatrics
5. Easy to use correctly by carers for
administration to young children
(>2 to <7-years)
6. Shorter, smaller device nozzle. Less
opportunity to irritate/damage nasal
membranes of children, particularly very
young children (>2 to <7-years)
7. Product retains prime once actuated
8. Consistent dose
9. Ability of patient to assess volume of
remaining product (reduces ullage)
Intra-nasal pump
Critical Quality Attributes (CQAs)
were identified to assure that the
pump provided the required
performance for the product. The
pump must be capable of metering
a consistent volume of the
formulation throughout the life of
• Issue 15
continued
Novel intra-nasal spray desired attributes
Dose volume (100µL) will be half that of the
established gold-standard market leader (200µL)
Removal of scented additives
Removal of phenyl ethanol and minimisation of
BKC (benzylkonium chloride)
The novel side-actuated device is designed for
self-administration by patients of 7-years and
older (see Figures 1 and 2). Specifically, with
respect to ergonomic design and lever force.
The device is designed to have the minimal
number of steps to use (shake, open, actuate,
close). The device is designed to have features
preventing accidental actuation
Side-actuated device facilitates carer
administration (see Figure 1). Actuation of
device by carer (or patient) does not require
contact between fingers/nose, as with currently
marketed devices (see Figure 2).
Re-designed nozzle (see Figure 3) and
actuation mechanism
Flexible stopper inside cap seals the nozzle,
preventing drain back and loss of prime
The pump is actuated with a consistent force,
and it is not dependent on the actuation force
(7-year child vs. 25-year old man). This
minimises potential operator variability.
There is a level indicator window incorporated
into device
the product (50µL). The pump must
be manufactured to appropriate
dimensional controls to assure a
reproducible fit to the neck of the
bottle and between the pump stem
and the nozzle. The pump was
constructed using materials
selected to have low potential to
leach into aqueous formulations.
Formulation development risk
strategy
The formulation was developed to
mitigate the anticipated risks
associated with a low dose
suspension formulation:
– In-homogeneity of drug product
arising from manufacturing
process or sedimentation/surface
enrichment of API over time
– Variability of spray characteristics
13
DEVELOPMENT OF A NOVEL INTRA-NASAL SPRAY PRODUCT
Figure 2. Side actuated (left) and
standard top actuated (right) nasal
sprays.
– As a result of changes in key
excipient attributes
– Inadequate protection against
microbial contamination, e.g.,
during ‘in-use’ dosing
– Patient discomfort (part of design
intent)
These risks were addressed by
inclusion of a suspending agent
that is sufficiently well
characterised/controlled to prevent
variation in the DSD of the drug
product, an isotonicity agent that
adequately controls the tonicity and
a robust, broad spectrum
preservative system that has been
optimised at the minimal effective
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14
levels, to minimise irritation,
particularly in paediatrics.
Conclusion
Using a combination of Quality by
Design (QbD) and specific
regulatory guidance, a novel side
actuated intra-nasal product was
rapidly developed and
subsequently commercialised.
Extensive focus on the design
intent and in particular,
patient/physician’s dissatisfaction
with currently marketed nasal
sprays allowed issues to be
anticipated and addressed at the
design stage. By approaching the
Figure 3. Carer administering
product using side actuated device
(26-month old child).
IN
AND
Edited by Tim Sandle
european INDUSTRIAL PHARMACY December 2012
continued
development holistically (from both
formulation and device perspective)
significant efficiencies were
introduced and problems could be
assessed and addressed rapidly
and effectively.
References
1 Guidance for Industry. Nasal Spray and
Inhalation Solution, Suspension, and Spray
Drug Products. Chemistry, Manufacturing
and Controls Documentation. US
Department of Health and Human
Services, Food and Drug Administration,
Center for Drug Evaluation and Research
(CDER), July 2002.
2 Soane, R.J., Frier, M., Perkins, A.C., Jones,
N.S., Davis, S.S., Illum, L. Evaluation of the
Clearance Characteristics of Bioadhesive
Systems in Humans, Int. J. Pharm., 178,
1999, 55-65.
3 Kippax, P., Huck, D., Levoguer, C., Virden,
A., Suman, J. Characterising a nasal spray
Formulation from Droplet to API particle
size, Pharm. Tech. Europe, February 2011,
34-39.
4 Guidance for Industry, ICH Q8(R2)
Pharmaceutical Development, US
Department of Health and Human
Services, Food and Drug Administration,
Center for Drug Evaluation and Research
(CDER), November 2009.
5 Guidance for Industry, ICH Q9 Quality
Risk Management, US Department of
Health and Human Services, Food and
Drug Administration, Center for Drug
Evaluation and Research (CDER), June
2006.
PHARMACEUTICALS
HEALTHCARE
and Madhu Raju Sag
hee
• Issue 15
SWOT ANALYSIS USING (GMA), a problem structuring
method, which we have reported
before in this journal4 that permits
GENERAL MORPHOLOGICAL the structuring and analysis of high-
dimensional problems. Such
problem complexes are often non-
ANALYSIS quantifiable, contain ineradicable
uncertainties and cannot be causally
Application to the Specials Sector for new simulated or modelled in a
Business Drivers meaningful way.

by Nasir Hussain, Bruce Garvey and Thomas Ritchey Process description using a
pharmaceutical case study
To test the validity of SWOT-MA™
T he humble SWOT (Strengths, Weaknesses,
Opportunities and Threats) is a remarkably simple
problem structuring framework. Ubiquitously taught in
process, an actual case example
involving a start-up niche generic
firm was considered for the
business schools, it is often the first port of call in many following focus question: “What are
organisations to map out tactical approaches for short to the most important factors to secure
near term projects. Since its introduction by Albert drug approvals within funding time
frame of 3 years”. In most cases,
Humphrey1 in the 60s, however, it has surprisingly regulatory authorities require clinical
undergone little revision – the lack of facilitation of testing in human volunteers of the
constructing a SWOT in the business setting, particularly generic drug against the original
the haphazard way of inter-relating the various elements innovator medicine whose patent (or
within each quadrant, has failed to realise the more correctly data exclusivity
period) has expired, i.e.
technique’s true potential. bioequivalence studies. In rare
circumstances, drugs of ‘well-
The authors are Founding Partners of Strategy Foresight, London, UK. established use’ and those that
Email: hussain@strategyforesight.org meet certain criteria (BCS Class 1)
are given ‘biowaivers’ particularly if
reference can be made to original
drug dossier5.
In their seminal paper, Hill and directional or causal linkage is Figure 1 shows a SWOT we
Westbrook2 from London Business assumed but merely mutual generated to address the problem.
School cited that seasoned strategy consistency in the arguments. CCA In all, 22 factors were identified in
professionals displayed similar is actually an essential element of the four parameters. This would
deficiencies when performing a General Morphological Analysis3 necessitate that 840 unique
SWOT analysis — “long lists (over
40 factors on average), general Strengths Weaknesses
(often meaningless) descriptions, a 1. Low overheads (e.g. head count) 1. Agency theory…
failure to prioritize and no attempt 2. Specialist testing outsourced 2. Limited experience of team in securing
to verify any points.” Most worrying the full process of licensing
was the universal finding that no- 3. Simple dosage forms (solutions, creams) 3. Limited staff – spread too thin
one subsequently used the outputs 4. Fixed private funds 4. Licensed manufacturing
5. Strong marketing & distribution network 5. Limited monthly budget/lack of flexibility
in the later stages of the strategy
6. Generating income from Specials 6. Limited key equipment e.g. HPLC
formulation. The more pertinent dealing which funds R&D
question remained: what, if any, was 7. Contracted out Specials manufacturing
the output?
Opportunities Threats
In this paper, we report a major
1. Further increase Specials operations 1. Regulatory guidelines being more strictly
improvement of how a SWOT interpreted
should be constructed and analysed 2. Diversify into more high-risk, high- 2. Same drug licensed by another company
by using the process of Cross reward dosage forms (e.g. suspensions) – reduced market share
Consistency Assessment (CCA), 3. Seek new indications of existing drugs 3. Bioequivalence trial costs escalate
transforming it into an actionable 4. Ability to raise funding 4. More data required for biowaivers by
framework. Here, each and every regulators at Day 105
5. Difficult to obtain original dossiers
suggestion from each quadrant is
compared pairwise to test for Figure 1: A SWOT analysis examining internal and external factors to be
compatibility. The CCA is similar to a taken into account by a niche generic drug firm to ensure drug approvals
cross impact analysis except that no within fixed funding timeframe (of three years).

european INDUSTRIAL PHARMACY December 2012 • Issue 15 15

SWOT ANALYSIS USING GENERAL MORPHOLOGICAL ANALYSIS continued

configurations be
considered by the
working group, an
onerous task given the
lack of time in many
organisations and,
more importantly, the
lack of a dedicated
computer software able
to capture the pairwise
assessments (there are
279 unique pairs for the
SWOT alone). Since a
3-dimensional problem
(pitting three
dimensions against
each other) can be
represented as X Y Z
columns, the four
dimensions of a SWOT
can easily be converted
into a 4-fold
morphological field as
shown in Figure 2.
The reader will Figure 2: The four parameters of a SWOT displayed as a 4-fold morphological field – or
notice, however, an 5-fold if one adds the output. In this example, there are 267 unique pairs and 3,360
additional output simple configurations (a configuration is a string of cells with each cell only appearing
parameter, namely the once – one shown).
Ansoff’s Matrix has
been bolted onto the
SWOT. This is an essential step to Figure 3 displays the CCA – threat” (e.g. increased
make sense of what one is trying to intersecting cells denoted by ‘X’ governmental regulation but lack
achieve with the SWOT-MA™ were deemed incompatible as of regulatory personnel within the
exercise, i.e. the output – the assessed by the working group firm)
principal objective of this paper, and whereas blank cells signified that – Weaknesses and Opportunities:
indeed of the SWOT. In this either the two conditions were “How can we circumvent an
instance, the workshop team compatible, or operated in two external threat to the project or
concluded that of the wide variety of different spheres of activity without organisation given an internal
management models available6, the impacting on each other. The role of weakness?”
product/market diversification objective facilitation and the Cross-analysing some conditions
model of Ansoff best suited the meaning afforded by comparing can become cathartic – for example
company’s near term aims and different parameter blocks cannot is it meaningful to compare internal
current activities (of specialised be over-emphasised. In this context, strengths and weaknesses,
provision of unlicensed medicines some of the questions asked during particularly when such conditions
and product registration). A more the CCA included: are mirror images that can offset
mature company in its business – Strengths and Threats: “Can we each other? For example, having
lifecycle may well have considered overcome a potential threat in the low fixed costs (strength) tolerates
another output such as the external environment with our the weakness of possessing limited
Horovitz’s framework, which internal strength?” (specialist) equipment (as such
evaluates cross-market/sector – Strengths and Opportunities: assets are relatively illiquid, and
expansion strategies by pitting the “Can we exploit an opportunity in require maintenance and service
dimensions of the ease of entry vs. the external environment with our contracts). In other instances, such
cultural fit7. internal strengths?” as pitting weaknesses against
For the CCA, the CARMA® – Weakness and Threats: “Given opportunities, it becomes a concern:
software reformats the our internal weaknesses, how can “What is the impact of having
morphological field into a matrix we circumvent external threats?”, limited equipment (a weakness) on
that easily allows a facilitator (e.g. or “What is the impact on the the ability to exploit a particular
the project manager) to conduct the organisation if the internal opportunity?” In the first situation, it
exercise with the project team. weakness reinforces the external there is no impact because each

16 european INDUSTRIAL PHARMACY December 2012 • Issue 15

SWOT ANALYSIS USING GENERAL MORPHOLOGICAL ANALYSIS continued

Figure 3: The entire problem space identified in a morphological field can be dramatically reduced by Cross
Consistency Assessment. Whereas in a morphological field the number of configurations increases exponentially with
each additional dimension (for example SWOT alone gives 840 configurations cf. 3,360 with the addition of the
Ansoff column), the number of Cross Consistency Pairs does not increase in proportion (179 vs. 267). For a relatively
small morphological field, few tens of pairs need to be ‘knocked out’ to obtain a manageable solution space.

condition operates in separate set
or universe (i.e. the conditions are
uncorrelated), whereas in the latter
case, there is a meaningful
comparison to be made.
Note that a third level of output
was also achieved with the use of
user-defined keys (K, S, and F),
which considered empirical
constraints (i.e. conditions that
would be possible if one only had
enough time, resources, etc). This is
an important facet as SWOT is an
evolving, dynamic framework that
needs to be revisited on a periodic,
basis. Using dedicated software,
notes can be taken for each
intersecting cell such that an
electronic audit trial of how the
decision was arrived is available for
sake of transparency, auditing, due
diligence, and timeline analysis.
Picking the winning strategy
Performing the CCA resulted in 23
unique configurations out of a
possible 3,360 combinations, a
reduction of over 99% of the entire
problem space – previous projects
have seen a reduction in over 99.9%

european INDUSTRIAL PHARMACY December 2012 • Issue 15 17

SWOT ANALYSIS USING GENERAL MORPHOLOGICAL ANALYSIS
with much larger morphological
fields that have contained 105 – 106
configurations. A deeper analysis of
strengths and opportunities yielded
some expected and more
significantly unexpected results. The
principal strength was in fact the
ability to fund company operations
from income being generated from
wholesaling and brokerage arm i.e.
7 of the 23 configurations contained
the cell ‘Specials income funds R&D’
– not particularly surprising given
that ‘cash is king’, especially when a
company has a fixed amount of
(private) funding. However, at the
start of the company’s founding, this
activity was too readily dismissed, as
the market for dealing in Specials
(see Box) was considered highly
volatile and uncertain8. The ability to
generate cash naturally allowed all
outputs to be considered except
‘Product Development’, a totally
unexpected result (diversification
was expected to fall out).
The point here is that multiple
scenarios can be considered, the
dynamic model can be driven from
the desired output (and what would
the required inputs to get to the
desired output state, i.e. reverse
engineering) and more importantly
the contrast, i.e. those cells which
do not show up. When the inference
model was considered in its entirety,
a hitherto unconsidered opportunity
emerged. Whilst applying for a
market authorisation of an
unlicensed product, it can be
supplied as a Special – this self-
funds the submission procedure
provided it is within the same
disease indication. Such gap analysis
is only possible using a very
structured and facilitated framework,
to which GMA is fully attuned.
Mapping and connecting the
entire landscape
Assessing multi-dimensional socio-
technical problems amongst
stakeholders without experienced
facilitation and purposeful software,
leads to sub-optimal decision-
making and waste of resources. This
is not surprising when one considers
18
how teams make decisions without
mapping out the entire ‘messy’
problem landscape. As observed by
Michael Pidd in his book Tools for
thinking 9: “one of the greatest
mistakes that can be made when
dealing with a mess is to carve off
part of the mess, treat it as a
problem and then solve it as a
puzzle, ignoring its links with other
aspects of the mess.”
Early stage companies face three
principal types of uncertainties –
commercial feasibility, technical
feasibility and the managerial ability
to execute, particularly when the
management team has not worked
together before10. In such situations,
the non-linear connectivity of
innumerable factors in a rapidly-
changing environment and the
subjective judgments when
interrelating even the most marginal
of factors are rarely captured or
facilitated in any meaningful manner.
Conclusion
In this paper, we have attempted to
describe how problem-structuring
methods such as GMA can vastly
improve analytical tools, such as
SWOT, in the context of business
management. GMA, however,
functions upstream in mapping the
totality of the problem space by
developing an exhaustive inventory
of all its possible solutions. By using
the CCA procedure, the synthesis of
internally consistent multiple
solution concepts (i.e. the design
space) can be isolated and tested
against possible outputs, intended,
and unintended, ahead of time.
We believe that such an approach
can be applied to other commonly
applied business management tools
where multiple parameters must be
considered. For example the
PESTEL framework (an analytical
tool to identify different
environmental factors affecting
business strategies) can be worked
in the manner described here to
develop the Opportunities and
Threats of the SWOT, and the
VRIO12 concept (resource capability
of the firm that determines its
european INDUSTRIAL PHARMACY December 2012
continued
SPECIALS
Some patients have special clinical
needs that cannot be met by
licensed medicinal products. So
that these special needs may be
met, UK law allows manufacture
and supply of unlicensed medicinal
products (commonly known
'specials') subject to certain
conditions, e.g. Viagra liquid
suspension is given to neonates
with pulmonary hypertension – the
original manufacturer, Pfizer, only
produce a tablet form, and for a
very different condition!
competitive potential) can assess
the internal Strengths and
Weaknesses. The various
configurations that emerge within a
smaller solution design space can
subsequently lead to the
development of possible scenarios,
which is the desired output in
business analysis and decision-
making frameworks.
References
1 SWOT Analysis. Available at
http://en.wikipedia.org/wiki/SWOT_analys
is (accessed 10 September 2011).
2 Hill T, Westbrook R. SWOT Analysis: It’s
Time for a Product Recall. Long Range
Planning 1997; 30: 46-52.
3 Ritchey T. Problem Structuring using
Computer-Aided Morphological Analysis.
J Operat Res Soc 2006; 5: 792-801.
4 Hussain N, Ritchey T. Wicked Problems.
Eur J Ind Pharm 2011; 31: 4-7.
5 Gupta E et al. Review of global
regulations concerning biowaivers for
immediate release solid oral dosage
forms. Eur J Pharm Sci 2006; 29: 315-24.
6 Van Assen M, Van den Berg G and
Pietersma P. Key Management Models.
London: FT Press; 2009.
7 Horovitz J, Kumar N. Strategies for retail
globalisation. Editors: HEC, IMD,
Templeton College and Oxford Mastering
Global Business. London: FT Press; 1998.
8 Colquhoun A. Special measures – time for
a healthy debate on specials
procurement. Pharm J 2010; 285: 481-88.
9 Pidd M. Tools for thinking: modelling in
management science. 2nded. Chichester:
John Wiley & Sons; 2003.
10 Improving the quality and quantity of
investment grade deal flow. City
University Research & Enterprise Unit;
2010.
• Issue 15
 This shift in focus made a
HOME HEALTHCARE considerable difference in the
questions we asked ourselves and
– it’s people not products that count patients, and on the design
solutions we conceived. The
by Dan Formosa packaging, for instance, isn't simply
a box to protect the medication – it

H ealthcare is not about the products that companies

create – it is about the ultimate effect the product
or service will have on someone's life. While this may
is an opportunity to walk patients
through the steps required to take
the medication properly. We opted
sound obvious, many medical companies seem to know for a format reminiscent of a
much more about their products than they know about storybook, with left and right flaps.
Rather than simply empty the
the patients their products are meant to treat. This isn’t contents on the table, our format
because they don't care or consider it unimportant. But put us in “design control” of the
many (and it’s probably fair to say “most”) medical components as the package is
researchers and engineers are not trained in even the opened by the patient, using an
basic elements of human behaviour, perception and organised and easy-to-understand
left-to-right sequence.
physical ability. This significantly limits the opportunity Also rare, even when design is
to fully realise the benefits of the pharmaceuticals or being addressed, is a good
medical devices that companies create. understanding of usability and
behaviour under varying levels of
Dan Formosa, PhD is a founding member of Smart Design, Barcelona, Spain, New stress. Even simple tasks such as
York and San Francisco, USA. taking a blood pressure reading
e-mail: dan.formosa@smartdesignworldwide.com. www.smartdesignworldwide.com can create anxiety in some people,
the so-called “white coat” effect.
Under stress, the mind and body
In view of the staggering statistics packages that we call well- work differently. So for all the
on non-compliance and dropout engineered-but-not-well-designed. thought and logic that may have
rates, everyone would benefit if Which means, yes, it may work been put into a task flow for
more attention were paid to these technically, but that accomplishes medical devices, that development
human-centred issues. Two topics little if patients are unable or often takes place without any real-
are of special interest in my design unwilling to use it. world context. This means a
research in the field of healthcare: Design in some cases can be the designer’s or engineer's logical
the impact of design on behaviour, most influential component in explanation of how a product works
and the ways in which people adherence to a regimen and and how it is supposed to be used
behave under stress. improvement in personal health. can make perfect sense in the lab –
This is important in view of the fact but not once the product is at
The impact of design that, for some people, even fear of home in a kitchen or bathroom. Its
Pharmaceutical companies rarely death may not be a sufficient use may sound simple enough in
consider the ability of design to motivator. theory, but unfortunately for the
influence patient behaviour for One example of “design for patient a medical company won’t
purposes of improving the efficacy compliance” that our firm Smart be sending a suitably trained nurse
of their medications or treatments. Design created involved the design or technician to every single home
Yet this presents tremendous of a new syringe for use with to explain how simple that product
opportunity for companies that Cimzia, a biologic medication for is to use!
have traditionally focused solely on rheumatoid arthritis (RA) patients.
the formulation of a medicine. Drug Because RA patients have limited Behavioural aspects
delivery devices and packaging strength and dexterity, self-injection From the many pleasant or
represent two critical touch-points can be difficult. While our design annoying examples in our daily
for patients that can contribute to team was enlisted to help re-design lives we all know that our
improved compliance. This not only both the syringe and the packaging, behaviours are influenced, for
helps the patient, it ensures we re-directed the assignment. We better or worse, by the products,
continued sales, a stronger brand set our focus not on the syringe and services and environments that
presence and better health package themselves, but on surround us. Home healthcare
outcomes. compliance. We asked ourselves products are no different. A
Skimping on either the device or what could we add to the design of patient's actions will determine to
the package can be a costly Cimzia's delivery system to help what extent a product or service
mistake. Our design group sees lots patients take their medication will work. His or her ability and
of examples of products and successfully? willingness to operate the device or

european INDUSTRIAL PHARMACY December 2012 • Issue 15 19

HOME HEALTHCARE
perform a task will ultimately
determine the reputation of that
product, service or brand and,
more importantly, whether the
patient is likely to comply with the
treatment.
Medical devices that look like
medical devices can be intimidating.
While the patient may be the only
person to use the device, he or she
may not be the only person to see
it. The same is true of packaging.
Visual impact should not be
ignored. A badly designed package
or medical device can make a
patient feel sicker than he or she
actually is, or it can give that
impression to others around him or
her. It can also prompt a patient to
hide the device in a drawer or
cupboard instead of keeping it in a
more accessible location that could
encourage use. Visual appearance
can also affect the willingness of the
patient to bring the device along
when travelling.
Many medical conditions are
serious, of course, and the
appearance of a product or service
should reflect that – but medical
products and services also need to
integrate neatly into peoples'
homes and lives. An illness does
not define a person. He or she is
very much the same person he or
she was before the illness. This is
one of the reasons why it is
advisable when developing medical
products to meet and get to know
patients personally. Without that,
it’s easy to fall into the trap of
imagining a patient, and grouping
him or her into an average that can
unnecessarily conjure up
stereotypical and misleading
images.
The first six months
Soon after the diagnosis of an
illness comes awareness of the
products, services or brands that
are available. As a patient's need
arises so does the willingness to use
those products. Healthcare
companies are in a unique position
to initiate emotional connections
with patients during the first few
20
months of an illness. This
relationship can be long term and
truly meaningful. Patients will be
most interested, curious and
apprehensive after being diagnosed
or started on a new treatment. That
start-up period, up to the point
where the patient is on “cruise
control,” where it has been worked
into their regular routine, deserves
special attention. That is, extra
special care should be taken early
on, when patients may be avoiding
use, reacting according to individual
preconceptions of how they think a
product may work, or concerned
about what effects they believe they
might experience.
The so-called out-of-box
experience – literally the first 20
minutes of use – is critical to
establishing a relationship between
the patient and the product, service
or brand. Failing to get started
within this time window, due to
difficulty of use or confusion, can
lead to product returns or refusal to
use the device or take the
medicine. For example, the number
of returned sleep apnoea products
can account for one-third of total
sales! The product may work as
designed, but the design was just
too difficult for patients, who were
confused about how to use it.
The days, weeks or months
immediately following first-time use
are also critically important in
shaping behaviours and attitudes.
Establishing proper behaviour early
is a project unto itself, and it should
be addressed accordingly.
Usability
I have identified the following
pattern, a hierarchy of usability.
People first respond according to
instincts, then preconceptions – the
latter being somewhat
unpredictable. Following that,
people will react to physical cues,
making three-dimensional design a
powerful tool. Communicating
proper use through 3-D design is a
much stronger driver than printed
words. A day-to-day example is a
door handle, a problem we have all
european INDUSTRIAL PHARMACY December 2012
continued
experienced. We are likely to pull
on a handle if it is shaped like a pull
handle, even if it is clearly marked
"push" – especially true when we
are in a hurry.
Following that, simple graphics,
simple text and other types of
colour coding can be effective in
directing behaviour and usability.
As for printed instruction sheets
or user guides – calling a friend, a
doctor or a toll-free number may
precede that option for many
people.
Home healthcare: It’s not
you, it’s us
There are many good reasons to
move healthcare tasks from
hospitals and clinics to the home.
Cost and convenience are at the
top of the list, and technology
continues to make this possible.
However, the move to the home will
be most effective when those
technologies are extremely usable.
The future of home healthcare,
and the speed and extent to which
it will develop in the next decade,
will depend on the ability of
patients to successfully use and
understand the products we
provide. Our ultimate goal is
extreme usability, allowing
untrained people to use the
advanced-technology medications
and devices we make available.
Companies have an opportunity
to help patients comply with health
regimens by realising that design
affects behaviour. Good design
takes into account both the physical
and psychological needs of the
patient. The fact that design can
heavily affect success or failure
means that influencing the attitudes
and behaviours of patients should
be well within the definition of
responsibilities of a product
development team. While this
approach should be followed
whenever a new technology
becomes available, there is also
opportunity to apply it to existing
medical products and technologies
– a move that can make us all
healthier now.
• Issue 15
regulatory review
The current review period has
seen a number of changes in the
regulation of medicines and
regulatory guidance in the EU,
International markets and the
USA.
United States of
America
Contaminated steroid
injections – USA Multistate
Fungal Meningitis Outbreak
The Centers for Disease Control and
Prevention (CDC), in collaboration
with state and local health
departments and the FDA is
investigating a multistate fungal
meningitis outbreak among patients
who received contaminated steroid
injections. Several patients suffered
strokes that are believed to have
resulted from their infections. The
investigation also includes fungal
infections associated with injections in
a peripheral joint, such as a knee,
shoulder or ankle.
FDA has confirmed that implicated
medication has not been exported to
any EU country.
Europe
Guideline (for comment) on
quality of oral modified
release products
This guideline concerns quality
aspects, especially pharmaceutical
development and in vitro testing, of
dosage forms in which the release of
active substance is modified. It is
restricted to gastro-resistance and
prolonged release oral dosage forms.
Pulsatile and accelerated release
dosage forms and delayed release
dosage forms with other principles are
not covered.
However many principles discussed
will be relevant to other modified
release dosage forms intended for
oral administration or via other routes.
Reflection paper on
medicinal product supply
shortages caused by
manufacturing/GMP
Compliance problems
This Reflection Paper is concerned
with public health crises that arise due
to unforeseen disruptions within the
european INDUSTRIAL PHARMACY December 2012
manufacturing process, caused by
manufacturing/GMP compliance
problems. While control and
supervision of the national market
remains a national responsibility, the
Network is increasingly looking to the
European Medicines Agency (EMA) to
develop and communicate
appropriate risk management
measures arising from unexpected
shortages in supply.
This Reflection Paper summarises
the lessons learned from previous
crises where the EMA had a
supporting or co-ordinating role, and
presents short and mid-term actions
that may allow the Network to
prevent, mitigate, and manage
shortages of important medicinal
products.
EU GMP Guide
The European Commission has
proposed changes to the EU GMP
Guide. These include:
Draft Concept paper on revision of
Annex 15
The need for this revision arises from
significant changes in the (GMP)
environment via ICH Q9 and Q10, the
updating of the guideline on process
validation, advancement in
manufacturing technology through
process analytical technology and the
continuous manufacture concept plus
many changes to other chapters and
Annexes.
Draft Concept paper on revision of
Annex 17
Originally the main foreseen
application area for Parametric Release
was sterility testing. Changes in GMP
consequent to the adoption of ICH Q8,
Q9, Q10 and Q11 and the recently
published guideline on real-time
release testing have broadened the
scope of the Annex.
MHRA
Public consultation (MLX
379): Transposition of
Directive 2011/62/EU (“the
Falsified Medicines
Directive”) into UK legislation
The Falsified Medicines Directive
substantially changes the European
framework concerned with the supply
of medicines, and may capture
• Issue 15
businesses that have traditionally not
been directly regulated e.g. internet
platforms based in the UK offering
medicines for wholesale or retail
supply, which may be considered to
be brokering or offering “sales-at-a-
distance”.
MHRA wins High Court case
on wholesaler dealing
MHRA has written to all those holding
wholesaler dealer’s licences reminding
them of the regulations following a
recent High Court case.
The core of the judgment is that in
order to comply with legislation
holders of wholesale dealer’s licences
(even if they also operate as a
pharmacy) must only obtain medicines
from another wholesale dealer licence
holder or from a licensed
manufacturer.
Notification of imminent
request for active substance
information
MHRA is contacting UK-based MA
holders to request data on active
substance imported into the UK for
manufacture. The aim is to minimise
the risk of potential shortages of
human medicines by identifying high
risk suppliers which may need to be
inspected by an EU authority as they
cannot meet the requirements for
certification by competent authority of
the exporting third country that the
plant manufacturing active substances
operates in compliance with EU GMP
or with equivalent rules
International
Revised PIC/S GMP Guide
The revised PIC/S GMP Guide (PE
009-10) will enter into force on 1
January 2013, as will the
corresponding changes to the EU
GMP. The revision concerns Chapter
4 & Annexes 6, 7, 11 and 13.
For further information on these and
other topics we suggest you refer to
the websites of relevant regulatory
bodies and to current and past
editions of “GMP Review News”
published by Euromed
Communications. To subscribe to this
monthly news service contact:
info@euromed.com
21
news from the EIPG
Welcome to our new Swedish
delegate
Following the move by Pär Tellner to
work for EFPIA in Brussels, the Board
of the Swedish Pharmaceutical
Association has appointed Marianne
Andersson, Regulatory Affairs,
AstraZeneca as the new contact
person for EIPG in Sweden.
We welcome Marianne and bid
farewell and thanks to Pär and wish
him every success in his new job.
Marianne’s email address is:
Marianne.andersson@astrazeneca.com).
The PHAR-QA (Quality
assurance in pharmacy
education and training in
Europe)
The second stage of the PHARMINE
project has been funded by the EU
and Nuno Moreira attended the
“kick off” meeting of the
Consortium in Brussels on 30th
October. The management of the 5
working parties and networks for
this exercise were agreed.
LifeTrain (An Innovative
Medicines Initiative (IMI)
Education and Training
Project)
In November, employers, course
providers and professional scientific
bodies were brought together with
the aim of producing an agreed
position paper on a European
Common Framework for continuing
professional development. As a
member of a regulated profession,
Jane Nicholson was asked to speak
on Developing a Competency
Profile for industrial pharmacists.
On-Course, another IMI initiative,
is now the most comprehensive
biomedical and medicines research
and development postgraduate
course portal in Europe (www.on-
course.eu)
Visit the website: www.industrialpharmacy.eu for PharmaTV and Quality by Design videos,
Regulatory Review, Financial Pharma News and other current items concerning Industrial Pharmacy
www.industrialpharmacy.eu
22
Regional Pharmacy Union of
Sofia Meeting in Bulgaria.
Claude Farrugia delivered a lecture
co-authored with Gino Martini to a
large meeting of pharmacists in
Sofia (of 900 registrants, 8-10% were
industrial pharmacists).
During Claude’s visit, Evgeni
Grigorov and Valentina Belcheva set
up a series of meetings with
academics including the Dean of the
Faculty of Pharmacy and the Pro-
Rector (who is a member of staff of
the Pharmacy Faculty), as well as
with leading members of the
pharmacy profession in Sofia from
the Regional Pharmacy Union of
Sofia (the largest of 7 chapters of
the Bulgarian Pharmaceutical
Union.)
European Medicines
Agency’s (EMA) Meeting with
Interested Parties 28th Nov.
The main topics of discussion were
the medicinal product shortages
due to manufacturing and quality
issues and the implementation of
the Falsified Medicines Directive.
The EMA update on their work
plan provided a summary of the
present position on GMP and GDP
guidance:
Final & Upcoming final guidelines
l GMP Guide Chapter 2 (2012Q4)
l GMP Guide Chapter 7
l GMP Guide Annex 2
l GDP Guideline – FP (EC-2012Q4)
Upcoming public consultations
l GMP Guide Chapters 3 & 5 + SWP
toxicological guideline (dedicated
facilities) (EC-EMA-2013Q1)
l GMP Guide Chapter 6 (EC-2012Q4)
l GMP Guide Chapter 8 (EC-2012Q4)
l GMP Guide Annex 15 (EMA
concept paper) (EMA-2013Q1)
l GMP Guide Annex 16 (EMA
drafting on going) (EMA-2013)
european INDUSTRIAL PHARMACY December 2012
l GMP Guide Annex 17 (EMA
concept paper) (EMA-2012Q4)
l GDP Guideline – API (draft to be
adopted Nov 2012) (EMA-
2012Q4/2013Q1)
Proposal to include definition of
importer and apply guidance to
importers, EC to consult Standing
Committee
l GMP Risk Assessment Guideline –
excipient (draft to be adopted
Nov 2012) (EMA-2012Q4/2013Q1)
l API Inspection Trigger document
– revision (draft to be adopted
Nov 2012) (EMA-2012Q4/2013Q1)
EudraGMP database
l New Module: GDP (FP & API) and
API registration (26 Feb 2013) –
regulators and users of API
l New Module: 3rd countries
inspections planning (Dec 2012) –
regulators only
The GDP guideline (FP) is being
updated to reflect current practice.
The GDP guideline has been
completely revised based on
numerous comments received
during the public consultation. The
chapter on transport remains. The
wholesale requirements for
transport have been revised.
The final GDP guideline (FP) will
come into force 6 months after
publication in the Official Journal.
Bureau meeting in January
2013
An EIPG Bureau meeting will be
held on Saturday 13th January. For
any items that members wish to
raise with Bureau members, please
contact me at:
jane@nicholj.plus.com
Jane Nicholson
• Issue 15
events
JANUARY 18-19 February 2013 – London, UK 26 February-1 March 2013 –
Advances and progress in drug Berlin, Germany
23 & 24 January 2013 – London, UK Pharmaceutical Microbiology
design
Social Media in the www.europe.pda.org/Micobio2013
www.drug-design.co.uk
Pharmaceutical Industry
www.social-media-pharma.com 19-20 February 2013 – London, UK MARCH
Real world outcomes strategy
28 & 29 January 2013 – London, UK 3-7 March 2013 – Sorrento, Italy
for pharmaceutical products
European Pre-filled syringes 3rd International Conference on
www.healthnetworkcommunications
www.prefilled-syringes.com Multifuncational, Hybrid and
.com/evidence
Nanomaterials
28-30 January 2013 –
26-27 February 2013 – Barnard www.hybridmaterialsconference.com
Cambridge, UK
Stability testing of Castle, UK
4-6 March 2013 – Copenhagen,
pharmaceuticals Cleaning validation
Denmark
www.rpharms.com/courses www.honeyman.co.uk
7th Annual FEI EMEA Front End
26 February-1 March 2013 – for Innovation
30-31 January 2013 – London, UK
London, UK www.IIRUSA.com/FEIeurope
Pharmaceutical Microbiology
www.smi.online.co.uk The business strategy of 12-14 March 2013 – Barnard
affordable medicines Castle, UK
www.healthnetworkcommunications Cleanrooms: Principles in Practice
FEBRUARY .com/generic www.honeyman.co.uk
5-6 February 2013 – Lyon, France
Modern biopharmaceutical 26 February-1 March 2013 – 21 March 2013 – London, UK
manufacturing London, UK Progress and challenges in
www.europe.pda.org/Biopharm2013 Innovations in development for pharmaceutical harmonisation
the biosimilar industry www.jpag.org
6-7 February 2013 – London, UK www.healthnetworkcommunications
Parallel Trade .com/biosimilarseu 31 March-3 April 2013 – Lisbon,
www.parallel-trade.com Portugal
26 February-1 March 2013 – 9th World meeting on
7 February 2013 – London, UK London, UK pharmaceuticals, biopharmaceutics
Assuring the Quality of Medicines World Generic Medicines Congress and pharmaceutical Technology
www.jpag.org www.healthnetworkcommunications.com www.apv-mainz.de

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european INDUSTRIAL PHARMACY December 2012 • Issue 15 23