Oral solid

dosage
surviving in
a new reality
APRIL 2016

ACHIEVING COST-EFFECTIVE
MANUFACTURING IN A
CHANGING OSD MARKET
 The world of
NEW PHARMA REALITY
pharmaceutical
manufacturing is
changing dramatically
A new
playing
field
Oral Solid Dosage (OSD) manufacturers are facing pressure on all sides to
make production more cost-effective. New high-potency drugs are launched
every year, with innovative delivery platforms such as sustained release,
sprays and chewing gum entering the market. At the same time, generic
manufacturers are increasing production capacity, while there is a general
shift to produce in emerging markets. Moreover, regulatory requirements
and health, safety and environmental standards continue to grow.
Increasing demand and competition
for oral solid dosage products force
manufacturers to optimise productivity
and cost-effectiveness. Fierce competi-
tion is driven by a dramatic production
increase, particularly in Asia, and by
the generic drug sector, where manu-
facturers increase production capacity
taking over propriety products. New
specialised drugs are introduced to
the market, including high potency
products, which put forward new and
sophisticated production requirements.
More products equals new
facility requirements
In 2014, the FDA approved 41 novel
drugs and biologics (including large
as well as small molecules), which is
the highest number in 18 years and a
52% increase from the 27 approved
in 2013. In 2015, 45 drugs were
approved, i.e. an additional 10%
increase compared to 2014. EMA
recommended 82 new products in
2014 (generics included) compared
to 79 in 2013 and 57 the year before.
In 2015, EMA recommended 93 med-
icines for marketing authorisation. This
includes recommendations for 39 new
active substances. More than 20% of
these applications are forecast to be
treatments for rare diseases. Today,
traditional pharmaceuticals/small
molecules/OSD products still make up
approximately two thirds of all medical
In addition to developments
in globalisation, increasing
GMP demands and price pressure,
pharma companies also face
challenges regarding flexibility,
time-to-market and cost on a
day-to-day operational level.
production in order to keep an accept-
able efficiency.
With the advance of new, more spe-
cialised products and an increase in the
number of APIs that are highly potent
(i.e. highly active pharmaceutical in-
gredients or HAPIs), comes a need for
high containment facilities, which can
help to avoid cross contamination and
ensure protection of operators and
environment when HAPIs are used.
The new trend within high contain-
ment facilities is small-scale continuous
manufacturing (or semi-continuous).
Continuous manufacturing requires
less space and supports efficiency
and low cost of goods. Continuous
manufacturing also enables a producer
of highly potent drugs to manufacture
these drugs in a safe way by eliminat-
ing manual transfer steps (bin to bin).
During the continuous manufacturing,
the product is permanently under sur-
veillance by process analysers to ensure
a high level of process control.
products (by amount not turnover).
These products are typically produced FDA and EU GMP promotes contin-
in large, dedicated facilities, but as uous manufacturing
patents for these traditional products Efficient technology transfer is becom-
expire, and new, smaller volume ing more and more important as the
products take their place, the need for number of new products increases.
large, single-production blockbuster These include transfers from:
facilities diminishes. More and more
new multi-purpose facilities are built or 1) lab to pilot scale and on to launch
old ones upgraded for multi-purpose and large commercial scale
2) one large scale production plant
to another
3) launch scale to low cost regions
With this in mind, NNE Pharmaplan
has developed an OSD design guide
that enables all engineers participating
in projects worldwide to work at the
same high level to master projects
across borders. This guideline ensures
that we can help our customer build
e.g. a facility in Asia with the same
standard and level of expertise as in
Europe. Project participants can call
on expertise from various experts,
specialist and SMEs from all over the
world. If required, engineers in Asia
can support projects in US or Europe
and vice versa. This might be relevant
if a ramp-up of resources is required
but not possible to get locally. This way
of working enables 24 hour engineer-
ing. All participants have the same
access and the same documents to
work with and use the same approach
and methodology.
This OSD design guide is based on
a model facility, which is also an
off-the-shelf offer for customers
requiring a standard OSD operation
established very fast. NNE Pharmaplan
has designed this facility to be com-
pliant with current cGMP regulation
related to FDA, EMA, PIC/S and CFDA
guidelines.
Site agility:
the key to your
continued success
Build your
market footprint
DEMAND / SUPPLY
The initial question you need to ask when plan-
ning for a new product introduction or up-scale of
capacity for an existing product is, How do I make
demand and supply meet each other while still keep-
ing risk, cost and time schedule under control?
The prime consideration in this regard is how fast you
expect to or need to introduce the product to the
market. This will also help you determine the capacity
requirements for future production system. However,
this demand forecast is often associated with high
uncertainties about volume and timing.
RAMP-UP STRATEGY
The ramp-up strategy should take into consideration
what it takes to 1) be ready for the first market
introduction, which is typically at a low volume, and
2) ramp up to high volumes later. The associated
capacity demand has to be established in a robust
but still flexible way, supporting changes in timing
and keeping both investment costs and operating
costs low.
Part of building the ramp-up strategy is also to
consider whether it should be a multi-product or sin-
gle-product facility. In order to keep a high return of
investment and utilise the capacity of the production
system as optimally as possible, you should consider
using the facility for producing more than one prod-
uct. While, this might present challenges with regard
to cleaning and cross-contamination, it is often worth
the effort to evaluate the option in order to ensure a
sound business case for de-selecting multi-purpose.
Besides increasing the capacity utilisation, multi-prod-
uct manufacturing will enable a larger organisation
to operate the facility, which in turn will present bet-
ter possibilities for obtaining critical mass and acquire
more knowledge within the organisation.
MAKE / BUY
Before establishing new production capacity, we
recommend that you look into the possibilities of
using a partner/contract manufacturing organisation
(CMO) for manufacturing the products. Especially for
new product introductions it is relevant to evaluate if
production capacity should be established in-house
or through a CMO.
In pharma operations your timelines are
shrinking. The only way for you to succeed
is to operate with maximum site agility
and flexibility. Your facilities need to handle
changes in production demands and quality
regulations fast and implement new knowl-
edge and technology faster still.
CAPEX / OPEX
Operational cost
Investment cost
Parameters to consider:
What formulation technologies are required/possi- Reduced Investment a flexible concept
ble considering the product profile? that allows you to make only net investments
Is formulation a differentiator? Does the formula- and wait with expansion until you have
tion make the product special compared to other established your market position.
products?
Strategic fit do you want to keep full control of
all parts of the supply chain?
Legal properties what is the impact from IP facility will impact the operational cost meaning that
rights, licenses and royalties? when you make design decisions you also make
Cost how are costs affected short and long significant decisions on the future operational cost.
term?
Capability do the required capabilities exist Consider the following:
in-house or do the capabilities have to be built If I spend 10% more on investment cost on cer-
from scratch? tain options will I then reduce my cost of goods?
Capacity is the capacity sufficient? If not what What will the cost of goods amount to for this
does it cost to establish sufficient capacity? new product?
Control strategy are special technology platforms How can I ensure that the cost of goods is in
or process analysers (PAT) needed to control the focus and optimised already in the design phase?
product and process?
Regulatory what are the regulatory constraints It might be better to spend a little more on invest-
related to using CMOs? ment cost if you end up with a lower total cost of
goods. We address significant input for these evalu-
If outsourcing is preferred you need to initiate a ations later in this newspaper, as it often starts much
sourcing process which includes identification of earlier in the development process than expected.
potential CMOs, evaluation and selection of a CMO Further, the working process will include design for
(perhaps by dividing CMOs into CROs, clinical trials LEAN ensuring that no waste is designed into the
and commercial production). facility by accident. The cost of goods includes:
Raw materials
CAPEX / OPEX Staffing cost and salary
It is important to develop a business case which eval- Energy and water consumption
uates investment cost and the operational cost to see Maintenance
if there is a positive net present value of the project. Consumables and other expenditures
Further, it is obvious that the design of the future Depreciation
RAMP UP STRATEGY
70
60
50
40
30
20
10
0
1 2 3 4 5 6 7 8 9 10
Large ramp up Sales forecast (high) Sales forecast (base)
Incremental ramp up Sales forecast (low)
 What to monitor Steering a process effectively, requires insight
on: 1) which process indicators (PI) can be mon-

Process development and how to act? itored in-line that predicts final product quality
attributes (CQA) and 2) What to do when PIs are

QBD APPROACH
Efficient, state-of-the-art processes
not where they should be i.e. how to adjust
critical process parameters (CPP). During process
development you need to identify PIs and estab-
lish relations between CQA and PI and between
PI and CPP in order to make a control strategy.

Product and process development Process justification

CPP, material Design space, Scale-up and Commercial Commercial

QTPP CQA CQA, PI ranges
Control strategy
tech transfer control strategy PPQ manufacturing

Define the quality Identify product Establish manufacturing process, identify Establish multivariate derived Define where and how to control CQAs Scale and site independent Control strategy updated to scale Process performance
target product profile critical quality attributes critical process parameters, material CQAs
ranges and acceptance criteria by CPPs and using PIs and dependent CPPs, ranges and include GMP controls qualification Batch production
and other performance indicators

INITIAL RISK ASSESSMENT, CAUSE-EFFECT IDENTIFYING TRUE CPPS ENSURING CQAS MEET EXPECTATIONS
UPDATED RISK ASSESSMENT AFTER IMPLEMENTATION OF THE COMMERCIAL CONTROL STRATEGY
CQA Material Blending Roller Milling Lubrication Compression Coating
input compaction
CQA Material Blending Roller Milling Lubrication Compression Coating
Identity input compaction
Appearance
Assay Identity
Impurity
Appearance
CU
Dissolution Assay
Low risk based on prior knowledge Impurity
Medium risk based on prior knowledge - should be considered further
High risk based on prior knowledge or not known - must be investigated
CU
Risk 1 ..
...

ISHIKAWA DIAGRAMME Dissolution

Blend LOD Particle size
API
API API
Diluents
Operator
Temperature
Relative humidity
Training
Number of revolutions
Manufacturing plant
Quality by Design understand
and control your process better
OSD products, e.g. tablets and
capsules, range from relatively simple
immediate release to formulations for
which the release of the API has been
modified to match a predefined target
product profile. In all cases, a robust
formulation is best achieved by apply-
ing a Quality by Design methodology
which in its essence combines science-
and risk-based approaches with a set
of useful tools for efficient process
development: Design of Experiments
(DoE), multivariate modelling, mecha-
nistic modeling and process analytical
technologies (PAT). Timely application
of these tools is key in establishing the
relationship between attributes of the
active ingredient, excipient function-
ality, processing environment and the
final drug product.
Analytical
Sampling
MCC Methods
Lactose
Other excipients
Blender type
Order of addition
Loading
Speed
Less critical
Medium critical
Process parameters Expected to be most critical
A systematic, science- and
risk-based approach
As a first step, the products overall
quality parameters are defined in the
quality target product profile (QTPP),
e.g. dosage form, dosage strength and
release characteristics. In the next step,
a cross-disciplinary team of experts
identify the attributes of the product
critical to the patient, CQAs (critical
quality attributes) and influencing
factors related to the raw materials
(excipient-CQAs) and processing
technology (critical process parame-
ters; CPPs). Excipient-CQAs and CPPs
are then ranked by criticality using
quality risk management tools such as
cause-effect diagrammes (traffic light),
Ishikawa diagrammes, process hazard
analysis (PHA), and failure mode effect
CQA
UDU /
content
uniformity
analysis (FMEA). Risk assessment is
an iterative process, initially relying on
prior knowledge* and then updated
on a regular basis as new process
knowledge is gained during develop-
ment and later tech transfer. Process
indicators (PIs) are also important to
consider as they reveal the current
state of the process in real-time using
instrumentation often already installed
in the process equipment. Through
underlying mathematical models the
PIs can suggest how to adjust the
CPPs and, if relevant, the attributes of
the raw materials, for the process to
remain in a state of control (i.e. CQAs
within acceptance criteria). Following
the first sets of appropriately designed
experimental campaigns, the design
space or the multivariate-based ranges
for the CPPs and/or material attributes
are specified and from here the first
control strategy is determined. The first
control strategy is usually restricted to
BENEFITS OF QBD TO THE PHARMA INDUSTRY
lab and pilot scale and needs updating
for tech transfer to commercial scale
and local site conditions. The control
strategies are essential outcomes of
QbD, as they define if relevant param-
eters are varied or fixed, in order to
ensure that product quality (CQAs) is
within specifications.
The QbD approach is encouraged
by health authorities to ensure that
processes remain in control, thereby
minimising the risk of drug shortag-
es and the impact it could have on
patients.
*The following reference describes how
a company effectively uses prior knowl-
edge to streamline the development of
roller compacted tablet products: Alles
et al. Presenting a rational approach to
QbD-based pharmaceutical development:
A roller compaction case study. Eur. Pharm.
Rev. 2013. 18(6). 17-24.
Low risk based on prior knowledge
Medium risk based on implemented controls
Quality The control strategy effectively handles known variability in the raw materials thus ensuring robust processes and a consistent product
quality.
Adapt to change The systematic methodology applied to process development, from its early stages to commercial scale, provides flexibility to predict
and proactively handle raw material variability that might otherwise compromise drug product quality. Besides the obvious advantag-
es to a commercially running process, this flexibility may also be valuable during drug development. For example, if the API route of
synthesis is being optimised in parallel with the formulation development work, unusually high variability in particle size and morphol-
ogy may be encountered. The QbD work already available may be used to predict and mitigate the impact of such changes on the
processability of the formulation.
Process validation (PV) FDAs guidance on process validation (2011) states that a successful validation programme depends upon information and knowl-
edge from product and process development. Batches manufactured across the different scales: lab-scale, pilot-scale and commercial
scale, shall no longer be handled as isolated tasks merely connected by a handover. A QbD methodology and the notion of design to
manufacture supports this lifecycle PV concept. Tools from the QbD toolbox, like risk assessment and analysis of correlation patterns
by e.g. chemometrics, can be used to link the information collected at various scales and provide true process understanding.
On-going (continued) Both FDA and EMA require a monitoring programme to demonstrate that the process remains in a state of control. With the increased
process verification level of process understanding gained from the QbD approach, the criticality of the material attributes and process parameters are well
(OPV/CPV) understood, thus simplifying the setup of an OPV/CPV monitoring programme.
Ownership and QbD is highly cross-disciplinary and the combined use of risk assessment and designed experiments enables the visualisation of often
collaboration highly complex processes. This increases each team members feeling of ownership and makes it easier to understand and communi-
cate either holistically or in detail the entire production process from raw materials to final product.
Maximising LEAN As a part of QbD-based product and process development, various attributes related to the formulation (e.g. lubrication content, gran-
outcome ule size) and CPPs have been explored and challenged as basis for selecting their optimal level(s). Maximising the process capability of
the commercial process using LEAN principles is therefore not restricted by non-optimal settings on the process equipment fixed during
development (e.g. inability to reach maximum press speed for tablet compression). QbD and LEAN combined is about doing the right
things right.
 Juggling The need for compliant and safe facilities, cou-
pled with the growth in low-cost production
investment from emerging markets, has made it critical for
OSD manufacturers to find a balance between
versus investment in modernisation and running
many of these risks and offset costs. This
includes in-facility transport of product
Modular engineer- Establishing the right capacity in the right time
is crucial, and one way to achieve this is to use
containers with automated guided vehicles
(AGVs) and automated docking to process
ing equals fast-track a modular approach, where facility design is
broken down into logical modules. This enables
equipment with high containment. projects, easy reuse parallel activities, giving the project additional

FLEXIBILITY
costs. Automation of processes can eliminate flexibility and making project changes more
manufacturing cost and high flexibility feasible.

Continuous manufacturing
Continuous processing can be the
solution for new products. It brings
benefits in production stability as well
as in product control. Continuous
processing is a perfect fit for small
and medium size output products.
Continuous processing also supports
processes that require containment.
As the process is closed from start of
batch with automated weighing until
the final tablet is ejected, no open
or manual product transfer to other
containers and units is required. Batch
systems are usually much bigger and
require more process rooms or square
metres and the approx. room ratio
is 1:4 m2 in favour for continuous. It
reduces the GMP footprint as well as
the space for technical area.
Batch production is typically suitable
for large volume mono-productions or
old existing products where re-register-
ing or product development and new
formulation would be too costly.
Nevertheless, equipment manufactur-
ers are currently developing contin-
uous production equipment to also
increase the size of the continuous
lines and continuous thus might be
possible for large volume production
in the long run. Currently, systems
with up to 200 kg/hr are available but
systems with estimated aimed batch
size of 400 kg/hr are expected to reach
the market soon.
NNE Pharmaplan cooperates with
leading suppliers for this technology
and has a track record of supporting
customers with this technology world-
wide as well as supporting the equip-
ment suppliers in further equipment
development. This knowledge also
enables us to provide our customers
with extensive, reliable support when
executing a project that involves
continuous manufacturing lines.
NNE Pharmaplan can support you
from the development of new prod-
ucts, industrialisation of new formula-
tions on this technology as well as fea-
sibility study to handover of a turnkey
solution in continuous manufacturing.
Continuous systems are very compact,
bring a high product reproducibili-
ty, demand less space compared to
batch operations and they require less
support equipment, less intermediate
handling and less intermediate storage
in between process steps.
Faster to market with continuous
manufacturing development
Data shows that new products devel-
oped using continuous manufacturing
are faster and cheaper to market
and consume less API for develop-
ment (typically only 10% compared
to a batch trial setup). Continuous
manufacturing is probably the next
major step in OSD manufacturing. The
advantages listed below have driven
several big pharma companies to
invest in continuous processing:
Fully closed process
Small GMP footprint
Reduced tech area
Reduced intermediate storage space
and low inventory
Continuous Manufacturing line CONSIGMA from GEA (from weighing via, granulation,
drying, sieving, blending, tablet compression)
High automation level based on PAT
and process modelling
Low variability of products high yield
Low operating cost low capital cost
Faster time to market
Lower development costs (reduction
of quantity of API)
Reduced scale up between labs,
development and production scales
Flexibility in production/supply size
(by adjustment of manufacturing
time)
Consistent and high quality of drug
products
Increased process control with PAT
(process analytical technology) is
key when implementing continuous
manufacturing
FACILITY LAYOUTS
Depending on the type of production
(single-product production, batch
production, continuous production)
there are different layout scenarios. A
layout usually reflects the demand of
the facility with a 100% load in the
future. Additionally, a layout/design
take into account possible future
expansion. These expansion possibili-
ties can be foreseen at an early stage
of planning. It can thus sometimes be
essential to determine the production
strategy of a facility. The production
strategy be it batch or continuous
is for example vertical product flow or
horizontal flow. Sometimes horizontal
flow is more compact and reduces
your GMP footprint, if you choose the
right process equipment. Expandability
can be an interesting challenge if the
ground the facility stands on is small
and restricted. Then a vertical flow can
be an advantage. NNE Pharmaplan has
an extensive track record of different
types of facilities tailored to the need
of customers and in compliance with
cGMP, EHS, and all regulatory bodies.
These facilities are built in Europe,
Asia, North and South America and
Africa.
The continuous line shown here en-
ables the continuous manufacturing a
product from weighing of raw material
to the finished tablet or capsule. In this
setup, with the diversion of product to
tablet press or capsule machine, you
can produce either tablets or capsules.
Due to the continuous process, you
cannot produce both formulations at
the same time. For traditional batch
manufacturing, we chose a spine
concept. The advantages of this
include easy access and easy extension
to either the right or left side of the Layout for a multi-purpose continuous
building. Additionally, we went with a manufacturing facility
second barrier concept to avoid cross
contamination and increase the safety
to avoid APIs and product migrating
through the building. The shown PAL/
MAL (personal/material air lock) setup
here can be built either as a sink or
bubble and is not considered as a
GMP step change but as a secondary
product safety barrier.
Layout for a standard multi-purpose batch
manufacturing facility

Real time release testing
Once you have developed your process
using a QbD approach and have a
clear understanding of material, CQAs,
CPPs and process indicators (PIs) and
you have controls in place to ensure
consistent product CQAs, it is possible
to replace conventional end product
testing by real time release testing
(RTRT). At NNE Pharmaplan, we have
experience in:
establishing real-time end-point
determination of e.g. blending,
granulation or drying processes
using e.g. NIR spectroscopy
establishing and getting design
spaces verified and approved for
flexible manufacturing
establishing RTRT programmes
where typical CQAs like identifica-
tion, assay, uniformity of dosage
units and dissolution are controlled
during processing
This information can then replace con-
ventional QC testing results for batch
evaluation and release.
For many CQAs depending on the
formulation and the specific process
typical process steps like blending,
granulation (dry or wet), extrusion,
drying, compression or coating are
critical. In most cases you can control
the CPPs and in-process material
CQAs using simple sensors as process
indicators (PIs) or more advanced
process analysers and control loops.
One example is blending: The process
is controlled by NIR and is automated
to stop once blending has reached its
endpoint rather than after a certain
time. Thereby you ensure blend ho-
mogeneity, which is often very critical
to both assay and content uniformity
(CU) and uniformity of dosage units
(UDU).
Dissolution is another example of
where heavy, time consuming QC test
can be replaced by a mathematical for-
mula and calculated even before the
tablet is coated. During development
of a fluid-bed granulation process, DoE
was used to understand the correla-
tion between tablet dissolution, CPPs
and material CQAs and to establish a
formula for calculation of dissolution.
The granule particle size measured in
real-time by laser diffraction, lubricant
specific surface area, lubrication time
and compression force were the vari-
ables in this formula. The model was
developed and the equation verified at
commercial scale. It is now approved
by health authorities and replaces
routine QC testing of dissolution.
Today not only big pharma is imple-
menting in-process controls and RTRT
for their processes. Examples are seen
both for new products where PAT
solutions often based on NIR, Raman
or laser diffraction and designed
during the development phase
and for legacy products where
historical data makes the foundation
for optimisation of the control
strategy to include PAT with or
without RTRT.
Controlling a process in real time is
often the biggest business driver.
No matter the type of batch release,
in-process testing provides the data
and knowledge to ensure that the pro-
cess remains in a state of control and
minimises the risk of costly surprises'
during commercial manufacturing.
For continuous processing, PAT and
real time process control are necessary
elements of the control strategy and
the information from these controls
can be used to not only control the
process and trace the process but also
for building an RTRT strategy.
Suppliers
NNE Pharmaplan has a close relationship with many of the suppliers of
OSD process and fill equipment. These relationships make it straight-
forward to design OSD facilities. During projects, these suppliers work
hand in hand with our process and building engineers to deliver a
successful project on both sides. NNE Pharmaplan has executed projects
that contained almost all existing OSD processes (storage, raw material
check, powder/solids handling, dispensing, sifting, milling, dry and wet
granulation in either high shear or low shear or fluid bed, extrusion,
drying, coating, blending, direct compression, roller compaction or
compression tableting and packaging).
In the past years NNE Pharmaplan has made projects together with the
top tear suppliers, e.g. GEA, Glatt, Bosch, Anhydro/SPX, Fette, Korsch,
GEA Courtoy, Waldner, DEC, Amixon and Ldige on almost all conti-
nents.
Standard OSD facility
NNE Pharmaplan has developed a standard OSD facility design for a
multi-purpose facility on the back of our many years of experience
building OSD facilities worldwide. The OSD design guide supports a fast
engineering approach and provides a standardised design document to
design OSD facilities for NNE Pharmaplan affiliates all over the world.
Every project participant uses the same approach and design documents.
One major choice needs to be made before executing a design; do you
want horizontal flow or vertical flow?
The standard OSD facility shown here is based on a horizontal flow in
spine concept (see layout multi-purpose batch manufacturing facility.)
This design comprises the possibility of producing multiple products in a
safe way compliant to all authority requirement. The design facilitates the
possibility to upgrade later to use potent APIs by using a second barrier
concept, here the PAL/MAL to minimise potential cross-contamination.
This design enables a flexible process setup also in the possible future
extension.
 Flexible and reliable
facility projects
anywhere in the
world
Maintaining high quality
in the completion of a high potent OSD
Roches OSD manufacturing facility
in Shanghai plays an important
role in strengthening the compa-
nys pharma business. Under the
management of NNE Pharmaplan
the project was completed within
an ambitious deadline and to high
quality standards.
Referred to as SHiP II short for
Shanghai High Potent plant II this
highly complex project aims to
enhance Roches existing high potent
production capacity. This is achieved
by adding a new facility adjacent but
connected to the existing high potent
oral solid dosage manufacturing at
the companys site in Shanghai and
improving the handling systems for
higher operator safety.
One of the purposes of the SHiP II
facility is to support other facilities
at the site especially in improving
the adjacent SHiP I through unified
purified water and high potent waste
When we deliver facility projects, we work
based on a global engineering model, Our
Model. This model ensures that everyone on
our projects works with the same well-prov-
en methods and best practices worldwide,
and they are flexible enough to adapt to
yours.
water system treatment. Additionally,
to accommodate the customers future
needs and safeguard against risk
the design included a site storage
facility with an explosion-proof room
for components of the production.
A strategically important project
SHiP II is one of the initiatives in
Roches 2018 master plan to develop
its Shanghai site and the first fully
integrated pharma hub in Asia Pacific.
Hans Tanner, Head of project manage-
ment China, explains the background
for the project: After a thorough
analysis and feasibility study conducted
during the Shanghai Site Master Plan-
ning Initiative in Q2 2012, it was clear
that we needed to build additional
highly active production capacity for
China and for global supply. All this
comes under SHiP II.
From the outset, it was a focal point
to maintain high quality standards,
while at the same time keeping to a
tight and fixed deadline in Q3 2015.
This meant that the primary objective
across every aspect of planning, design
and construction was to maintain
quality without losing momentum.
Working effectively across borders
The project began more than 10,000
kilometres from Shanghai in Basel,
Switzerland where the pre-concept
was started in August 2012. NNE
Pharmaplan staffed the pre-concept
with nine process engineers from Swit-
zerland and four Chinese architects/
engineers based in Shanghai. As the
pre-concept was carried out in Europe,
a key challenge was how to transfer
this knowledge to China. Although
time pressure was mounting, it was es-
sential to achieve this transfer smooth-
ly and seamlessly without affecting the
schedule or quality.
The design was transferred to China
at the start of basic design (BD). The
core members of the original European
Customer
Roche Shanghai, China
Facility/area
The facility boasts 2,500 m2 produc-
tion area distributed on 2 levels.
Challenge
Time pressure and a tight deadline
Solution
Agile and flexible engineering
Project duration
August 2012 2015
Services provided
Pre-concept design, conceptual
design, basic design and EMCMQ (en-
gineering, procurement, construction
management and qualification)
team continued to provide support
throughout the project and two
European engineers were on site to
support during the equipment installa-
tion and qualification phases.
From the beginning, Roche put much
focus on involving the users in order
to optimise project solutions. Klaus
Illum, Head of Project Governance at
NNE Pharmaplan elaborates, Early
planning of user involvement as well
as early dedicated inspections by the
user, made the transfer from project to
user very smooth.
Despite a number of challenges along
the way, NNE Pharmaplan was able
to successfully complete the SHiP II
project in early 2015. As a result of
this achievement, NNE Pharmaplan
was awarded a new project at Roches
campus, involving many of the SHiP
II engineers who are leveraging their
experiences and lessons learned from
SHiP II in the new project.
NNE Pharmaplan NNE Pharmaplan is active participating
in major pharmaceutical associations and
Bad Drkheim, Germany and the new
ISPE Containment Handbook was released
and ISPE containment authority panels. We are first in line when
new drafts, handbooks and guidelines are
NNE Pharmaplan was present. Only a few
weeks after its release, it was clear that the
workshop in presented. industry consider this book as a guideline
and as a new standard to be applied.
November 2015 So when ISPE Affiliate Germany, Switzerland
and Austria held a containment workshop in
Containment HAPI
Handling highly potent active pharmaceutical ingre- The frequency of a task/process future unknowns need to be considered as provisions
dients (HAPIs) in oral solid dosage (OSD) production The duration of task to be implemented from the beginning. In addition
accelerates the need to upgrade existing facilities or The transmission path (skin, inhalation, etc) to the standard containment task, NNE Pharma-
build new ones. plan has executed project where protection strategies
Whichever type of protection and containment you for operators and environment against radiopharma-
OSD API PRODUCTION SERVICES go with, the selection must be the result of a detailed ceutical contamination was required. These projects
Highly-potent API containment strategies chemical risk assessment (room by room, process step are rare but have been executed to our customers
HAPI risk assessment by process step, by type of product, exposure time highest satisfaction.
Definitions of information about hazardous and per operation, etc). Often the choice of equipment
other pharmaceutical processes and control strategy is made by an interdisciplinary 1)
Only inhalation risk assessment is considered
 Necessary containment equipment solutions team with competences within process, building,
HVAC, utilities, waste. It is important to decide if
Safety and regulatory compliance are key factors
when dealing with highly potent APIs used for e.g.
oncological dosage forms. The main challenge lies in
protecting the production staff and the environment OEL: OCCUPATIONAL EXPOSURE LIMIT Risk assessment if a
while also protecting the product from contami- OEB: OPERATIONAL EXPOSURE BAND Isolator is necessary
nation and complying with local regulations. NNE CAT: CATEGORY ACCORDING TO ISPE for open handling
Pharmaplans engineers provide expertise within GMP
requirements and highly potent technology. We help G 4 (5) < 1 g/m3 Very high pharmacological
you to design and construct facilities that produce and toxic effect
highly potent OSD APIs in a safe and contained
manner that complies with all local and international High pharmacological
G 3b (4) 1-10 g/m3
regulation and requirements. NNE Pharmaplan has and toxic effect
built multiple facilities in the past years that involve
handling of potent material down to less than Medium pharmacological
30 ngr/m3 (OEB5) and has been involved in upgrades G 3a (3) 10-100 g/m 3 and toxic effect
to bring existing facilities to a state-of-the-art level to
ensure safe operations and avoid contamination and Low pharmacological
migration of highly potent API in a facility. Measures G 2 (2) 100-1000 g/m3 and toxic effect
for required operator protection mainly depend on :
The danger of the product (OEL) Very low pharmacolog-
G1/1 1000-5000 g/m3 ical and toxic effect
The physical characteristics of the product (liquid,
powder, tablet, etc)
The type of process (dispersive or not) CAT / (OEB) OEL Effect
The amount of product handled
CHEMICAL INHALATION RISK ASSESSMENT FOR HIGH POTENT PRODUCT
NNE Pharmaplan has developed a tool to make a chemical risk assessment chemical database that contains a collection of various potent APIS including
for high potent products. The tool enables to quickly make an inhalation their properties according to their material safety data sheets (MSDS). With
risk assessment at different process steps where highly potent chemicals are the output of this tool, NNE Pharmaplan can engineer the right solution to
used. It is part of an initial health, saftey and environment (HSE) evaluation if each process according to the occupational exposure limit (OEL) require-
potent ingredients have been identified. This tool has a background in a ments.
 A successful technology
transfer has the end
goal in mind from the
beginning
Tech transfer
In the attempt to continuously discover new
products as well as next generation products,
the industry is developing new product
candidates at an accelerated rate.
In 2014, the FDA approved 41 novel drugs and
biologics (including large as well as small molecules),
which is the highest number in 18 years and a 52%
increase from the 27 approved in 2013. In 2015, 45
drugs were approved, i.e. an additional 10% increase
compared to 2014. EMA recommended 82 new
products in 2014 (generics included) compared to
79 in 2013 and 57 the year before. In 2015, EMA
recommended 93 medicines for marketing authorisa-
tion. This includes recommendations for 39 new ac-
tive substances. More than 20% of these applications
are forecast to be treatments for rare diseases.
In addition to the increasing number of new approv-
al, generic versions of major blockbuster products
will likely become available in different markets in the
near future due to patent expiry. Demographics and
local market forces in emerging markets such as the
public-private partnership models drive the business
of promoting access to these products. This places
emerging markets in a position to lead the way in the
innovation of flexible, multipurpose and cost-effec-
tive manufacturing.
The technology required for local manufacturing is
often sourced from established technology providers
that already have ongoing programmes for devel-
oping and updating products. Ensuring successful
technology transfer from these technology partners is
crucial for a fast establishment of local pharmaceuti-
cal manufacturing.
Pharmaceutical products can be highly complex and
the notion that the product is the process and the
process is the product is widely acknowledged
by the regulatory bodies. This underlines the impor-
tance of product and process knowledge and project
execution to support successful technology transfer
and market entry on time.
NNE Pharmaplan was born and raised with the pro-
cess and production understanding of a pharma-bio-
tech company. Our global coverage coupled with
our vast project experience has provided us with the
competences and know-how to execute on matters
such as technology transfers and process qualifica-
tion with great success. Technology transfers involve
several cross-disciplinary elements ranging from GMP
compliance, regulatory affairs and technical know-
Emerging markets represents the major
growth engine of the global pharmaceutical
industry with a high unmet demand and very
little local manufacturing. To unlock this huge
potential, youll have to look at the enablers
and critical points in technology transfer.
how as well as human resources which may not be
available in the existing organisation.
Thanks to our global presence, NNE Pharmaplan
can support your technology transfer by making an
interdisciplinary team available covering several areas
including:
GMP compliance
Regulatory demands
Product understanding
Technology and process knowledge
EHS compliance (e.g. containment)
Control strategy
Supplier evaluation
Supply chain management
Start-up of production and qualification
Project
TECHNOLOGY TRANSFER PLAYBOOK - LINKING BUSINESS NEEDS WITH
PRODUCT UNDERSTANDING AND PROCESS KNOWLEDGE
Business
Product
Target product profile
Process
Facility and technology
Fill finish
NNE Pharmaplan masters all aspects of the fill finish
world (blistering, wallets, bottles, sachets) and
our track record for projects related to fill finish is
impeccable: We have executed countless projects
involving blistering ( plastic and aluminums), vial
filling, blow fill seal, cartridges filling, bottle filling,
inhaler devices, cartooning, boxing, wrapping
The goal of technology transfer
activities is to transfer product and
process knowledge between
development and manufacturing,
and within or between manufacturing
sites to achieve product realization.
This knowledge forms the basis for
the manufacturing process, control
strategy, process validation approach
and ongoing continual improvement
(ICH Q10)
Market
and palleting. The expertise is extensive and we
manage projects in sterile, aseptic, containment
and even nuclear environments. NNE Pharmaplan
has more than 50 specialists worldwide to sup-
port you with your task and challenges. We have
strong relationships with all suppliers of fill finish
equipment and cooperate closely with these
suppliers to ensure that you project is a success.
End-to-end support
from consultants
specialised in pharma
Quality and compliance
NEW APPROACH
TO PROCESS VALIDATION
Process validation is not only a
regulatory requirement, but also very
good business. If you understand the
process you can predict the outcome
and ease optimisation of the process
and product. Of course it also proves
that the process is safe and effective.
Process validation is about collecting
and evaluating data from the process
design stage through commercial pro-
duction. The data establishes scientific
evidence that a process is capable of
consistently delivering quality products
meeting its predetermined specifica-
tion and quality attributes. Process
validation of a product lifecycle can be
divided in three stages as illustrated in
figure 1.
Ref. 1. US Food & Drug Adminis-
tration, Guidance for Industry, PV:
General Principles and Practices,
guideline, 2011 and 2. EMA Guide-
line on process validation for finished
products, EMA/CHMP/CVMP/QWP/
BWP/70278/2012-Rev1.
In order to consistently deliver quality
products and ensure the safety and
efficacy of your products, quality must
be built into the design and manufac-
turing process at every step right from
the beginning. This can only be done if
process understanding is present.
Process understanding is essential in
supporting qualification and process
validation activities. Process under-
standing and proof of mitigation effec-
tiveness can be achieved by applying
Six Sigma tools such as Gage R&R
studies of the measurement system
and Design of experiment (DoE).
RISK-BASED APPROACH
Process understanding is directly linked
to risk. Hence quality risk management
play an important role as it aims to
diminish the risk inherent in any phar-
maceutical production.
NNE Pharmaplan can help set direc-
tions and strategies for companies
Our pharma consultants are with you
all the way from project idea through project
execution to ramp-up and beyond. Through
focused pharma engineering we help you
obtain and maintain an optimal production so
you can always deliver on demand.
wishing to pursue the implementation FUTURE REQUIREMENTS 
Objectiveness of systems associated
of science- and risk-based process QUALITY METRICS with the manufacture of
validation for new and existing FDAs new quality metrics programme pharmaceutical products.
products. is supposed to be a tool to help plan- 
Based on future quality metric
ning GMP Inspections. reports, FDA will use a risk-based
WHERE TO START AND TIMING approach to plan inspections.
The new process validation approach 
The objective is to measure the 
The UK healthcare authorities are
applies to both new and legacy prod- quality of a products or processes. using a similar risk based approach
ucts. For new products the process 
Quality is the fitness for intended to plan the frequency of GMP
validation approach should be initiated use of the product, relevant to inspections.
already during development of the patients and quality. It is a measure 
The proactive nature of the future
products. This may e.g. require addi- of a sites ability to manufacture will be based on science and risk,
tional training and maybe even new products fit for intended use. It is having the patient as the main
resources. also an objective measure of the focus. The regulation are changing
effectiveness including the to be more forward looking and to
For legacy products, stage 3 must be pharmaceutical quality system. facility innovation.
applied based on prior knowledge and
a risk assessment must be established
identifying critical quality attributes TYPICAL CHALLENGES With a workshop which will kick
(CQA) and critical process parameters To learn about the new approach- off and deliver a process valida-
(CPP) for legacy products. Identifica- es and to understand the impact tion strategy plan and identified
tion of a control strategy (simple or on your organisation list of deliverables
advanced) must be performed and the
data obtained must be trended using To learn how the new approach With training and/or execution
statistical tools. impacts development projects of risk assessment, statistics such
and legacy products as DoE and stage 3 monitor-
The question is where to start with ing program.
legacy products? A good starting point How can NNE Pharmaplan help?
is to make a priority list of all your With a training programme With training and education
legacy product, including justification adjusted to your specific situation within process validation in gen-
of the priority. eral (e.g. ECA, ISPE, FDA).
FIGURE 1
1. Process design
The commercial process including the control
strategy is defined based on knowledge gained
through development and scale-up activities
3. Ongoing/continued process verification
Ongoing assurance is gained during routine
production and monitoring that the process
remains in a state of control. 2. Process validation
The process design is evaluated to determine if the process
is capable of reproducible commercial manufacturing. It can
be divided in two sub-stages: A) process validation design
and qualification of the facility, utilities, equipment and
processes and B) process performance qualification
Global reach
local knowledge
Offices
Our oral solid dosage experts
Jacqueline Vu
Global Technology Partner
Jacqueline Vu has worked in
international pharmaceutical
engineering for more than 20
years. She has broad experience
of working with feasibility and
front-end studies as well as with
conceptual design, detailed
design, logistics and selection of
material handling equipment and
assistance to construction.
Jacqueline possesses extensive
oral solid dosage (OSD)
project experience with a
particular focus on automated
OSD plants (automating material
handling systems, gravity flow,
closed systems and OEE
improvement).
Boston
(Cambridge)
Research Triangle Park
(Morrisville)
Sven Oliver Gottlieb
Principal Consultant
Oliver has worked with oral
solid dosage (OSD) for more than
13 years. This includes project
management, engineering and
operational tasks within a phar-
maceutical engineering company
and a pharmaceutical company.
Oliver possesses extensive OSD
project experience and has
worked with feasibility and front-
end studies as well as with con-
ceptual design, detailed design to
construction, troubleshooting and
de-bottlenecking. He currently
works in the process technology
consulting group and offers
consultancy services pertaining
to OSD and containment. He is
responsible for establishing the
global OSD design guide that
sets the global NNE Pharmaplan
standard for OSD facility design.
Copenhagen
Kalundborg
Hillerd
Brussels
Frankfurt
(Bad Homburg)
Chartres
Paris
Lyon
Basel
Montreux
Morten Alles
Senior Consultant, PhD
Morten has 7 years of experience
in the pharmaceuticals industry
and is a dedicated, results-driven
oral solid dosage (OSD) expert
with a Masters degree in phar-
maceutical sciences and a PhD
in process analytical technology
(PAT) for pharmaceutical
applications.
Morten has practical experience
of implementing Quality-by-De-
sign (QbD) methodology in
the development of new solid
dose form products in order to
improve effectiveness (right the
first time) and efficiency (e.g.
reducing time spent on early for-
mulation development) and also
in troubleshooting and improving
performance of commercial
tablet production.
NNE Pharmaplan is an international company specialised
in pharma engineering. We help pharmaceutical
companies bring products to market by providing
flexible, compliant and future-proof solutions.
We have close to 2,000 professionals delivering global
knowledge and best practices, all dedicated to supporting
our customers globally and on local sites. Through
focused pharma engineering we enable our customers
to deliver on demand.
nnepharmaplan.com
Tianjin
Teda
Shanghai
Bangalore
Line Lundsberg-Nielsen
Principal Consultant, PhD
Line Lundsberg-Nielsen is a
physicist and has worked in the
pharmaceutical industry for 20
years. She has a wide experience
from both R&D and Manufactur-
ing been working with science
and risk based approaches such
as Quality by Design, Process
Analytical Technology and
Process Validation.
Line has practical experience
from developing, implementing
and getting regulatory approval
of a control strategy for an OSD
based on PAT including NIR and
with full Real Time Release
Testing of the product. She is
familiar with the regulatory pro-
cesses used for CMC approval
in both FDA and EMA and for
lifecycle maintenance.