Professional Documents
Culture Documents
DISSERTATION
of the University of St. Gallen,
School of Management,
Economics, Law, Social Sciences
and International Affairs
to obtain the title of
Doctor of Philosophy in Management
submitted by
The University of St. Gallen, School of Management, Economics, Law, Social Sciences
and International Affairs hereby consents to the printing of the present dissertation,
without hereby expressing any opinion on the views herein expressed.
The President:
For Cristina.
Acknowledgement
This dissertation is the final result of over four years at the Institute of Technology
Management of the University of St.Gallen. During that time I had the chance to be
involved in various interesting research and consulting projects and I had the opportunity
to function as teaching assistant of two lectures. All this was an extraordinary experience.
It was all enabled by my supervisor Prof. Dr. Thomas Friedli, who provided guidance
and support when needed but allowed to work independently whenever wanted. I very
much appreciate his mentorship and all his professional and scientific advices. Also, I
thank Prof. Dr. Urs Fueglistaller for his interest in my research and for agreeing to act as
co-supervisor.
Furthermore, I enjoyed the pleasant environment at the Institute of Technology
Management. I had numerous creative and productive discussions with the whole team.
Special thanks go to Andreas Mundt, with whom I worked on different projects and
seminars, and Matthias Gtzfried.
I thank my family for the outstanding support and encouragement during my studies and
especially my time in St.Gallen. Special thanks go to my father Dr. Ren Ziegler for his
critical reading of this dissertation.
Finally, I thank my love, Cristina, for all her patience, endurance, support, and constant
motivation. Without her, this dissertation wouldnt have come to an end.
Summary
Current figures from the pharmaceutical industry show a clear trend towards ever rising
costs and duration of new product development. In parallel, fewer product candidates get
through clinical development. This can be summarized simply as an R&D productivity
crisis. The result is increasing time and cost pressure and results in fewer resources being
allocated for the development of manufacturing processes. As soon as efficacy and safety
studies are accepted by regulatory agencies, commercial production starts with whatever
production process had been used during development. Delays right before launch have a
direct effect on the remaining time the product is protected by patents and thus on high
margin sales.
As a result it can be observed that many newly introduced products are produced by
highly inefficient manufacturing processes. Poor processes lead to excessive
manufacturing costs which could easily be avoided by changes in the development
process.
In the past it was shown in other industries (e.g. electronics and machinery) that the
problem mentioned above was solved to a great extent by using an approach called
integrated development. Basically this means involving production early during
development in order to ensure that processes can be transferred to commercial
production very smoothly and ideally without any adaptations.
In this dissertation it is shown how to adapt an integrated development approach to the
pharmaceutical industry. The result is a process model surrounded by a framework that
extends the scientific knowledge about integrated development and is at the same time
applicable in practice.
Zusammenfassung
Aktuelle Zahlen aus der pharmazeutischen Industrie zeigen, dass die Entwicklung von
neuen Produkten immer lnger dauert und immer mehr kostet. Zudem schaffen immer
weniger Produkte die Hrde der klinischen Entwicklung. Man spricht schon fast von
einem Produktivittsproblem der Forschung und Entwicklung. Dieser Zeit- und
Kostendruck fhrt dazu, dass immer weniger Ressourcen fr die Entwicklung der
Produktionsprozesse
aufgewendet
werden.
Produkte
werden,
sobald
die
durch
den
Einbezug
der
Produktion
sichergestellt,
dass
die
Table of Contents
XII
Table of Contents
Table of Contents
XIII
List of Figures
XVI
List of Figures
List of Figures
XVII
XVIII
List of Figures
List of Tables
List of Abbreviations
ADME
API
B2B
Business to Business
B2C
Business to Customer
CE
Concurrent engineering
CF
Cross-functional
CFT
Cross-functional teams
CMA
CMC
CMO
CPP
CQA
CRO
DFSS
DOE
Design of experiment
EMA
e.g.
et al.
et alii
FDA
FMEA
Gate
Hrsg.
Herausgeber
XXII
List of Abbreviations
HSG
i.e.
IP
Intellectual property
IPC
In-process-control
IPD
ITEM
MS
Milestone
NDA
NME
NPD
OEE
OPEX
Operational excellence
OTC
Over-the-counter
PAC
Post-approval change
PAT
Pharmaco
Pharmaceutical company
POC
Proof of concept
PPQ
QA
Quality assurance
QbD
Quality by Design
QC
Quality control
QFD
R&D
RACI
RBV
List of Abbreviations
XXIII
SOP
TPP
TPQP
1 Introduction
This chapter builds the practical base for the research reported in the present dissertation.
Furthermore, it introduces and defines special terms and describes the research
proceeding.
First, the motivation and the practical relevance are described. This is followed by our
definition of the pharmaceutical industry and by the explanation of other terms. In the
fourth sub-chapter the research goal and questions are introduced. Finally, the research
design is laid out, explaining the general research proceeding and the theory this research
bases on as well as the structure of this dissertation.
1.1 Motivation
There are many scientific publications to the subject of New Product Development and
its advancement, Integrated Product Development (Kamrani and Vijayan, 2006;
Koufteros et al., 2005; Gerwin and Barrowman, 2002; Krger et al., 2010; Boyle et al.,
2006; Naveh, 2005; Yeh et al., 2008). Supporting tools and methods are described and
their impacts are shown by measurements (Yeh et al., 2008). A great portion of the
existing literature deals with the B2B domain, which is driven by different motives than
the B2C domain (Gerwin and Barrowman, 2002). The remaining literature about
integrated product development in the B2C domain is mostly limited to the mechanical
and electronic industry (Tessarolo, 2007). In other words: there is almost no literature to
this subject focusing on the pharmaceutical or related industries. The main reason is the
substantially more complex development process1. This rather large and especially
relevant industry should no longer be underrepresented in literature.
Furthermore, most existing literature to this subject addresses the measurement of how
various methods and tools impact the development performance (Yeh et al., 2008). The
optimal practical implementation is rather not discussed. Only a very limited amount of
The development process itself is not very different from other industries. However, the main difference and
increased effort is mostly due to high regulatory requirements.
Introduction
examples for the efficient elaboration of the interface between development and
production can be found in the international research community (Vandevelde and
Dierdonck, 2003). Literature is lacking a design model contributing to a higher
understanding of this interface.
The role of launch sites (see chapter 1.3.2) during development is also not sufficiently
described in the literature. So far, there is no model for the collaboration between launch
sites and development, which are in many cases spatially separated.
The FDA initiative Quality by Design (QbD) addresses a contemporary and relevant
concept that is rather new to the pharmaceutical industry (FDA, 2007). Because of its
novelty, there are rather few scientific publications about it. However, a theoretical
description helps to thoroughly understand the initiative and to apply it both effectively
and efficiently.
200
38
40
35
34
28
26
26
150
131
120
108
100
88
35
31
29
127
128
135
134
136
138
141
144
147
149
30
25
+70%
96
20
15
10
Number of NMEs
issues.
5
50
2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
NMEs
Total industry
NMEs: New Molecular Entitites. It stands for an entirely new (chemical, but not biotechnological) product. It
does not include products with changed dosages or new therapeutic applications and is comparable with the first
submission of an active ingredient.
3
Time to develop a drug (years)
Introduction
15
14
13
+28%
12
11
0
1996 1998 2000 2002 2004 2006 2008 2010
1,300
1,500
802
1,000
500
+842%
318
138
0
1975 1980 1985 1990 1995 2000 2005 2010
4.6
3.4
3.7
4.9
4.2
3.7
3.8
2.3
+65%
2
0
2004 2005 2006 2007 2008 2009 2010 2011
15
10
-34%
5
0
1996 1998 2000 2002 2004 2006 2008 2010
Figure 5: Time of patent protection after product launch (CMR International, 2008).
Introduction
Since quite some time a trend has emerged in the pharmaceutical industry: the time to
develop a new product from the discovery of the active ingredient to the final drug
product has increased continuously (Figure 2). This coincides with increasing
development costs per NME (Figure 3 & Figure 4) caused on the one hand by longer
development times due to constantly intensifying regulatory requirements, and on the
other hand by increasing safety requirements of pharmaceutical products (Basu, 2010a).
In the pharmaceutical industry new substances are filed for patent protection very early
in the R&D process, often during discovery and before the beginning of product
development. Thus, longer development time results in a shorter patent protection period
(Figure 5) during which it can be sold exclusively before competitors or generics
manufacturer can imitate it (Basu, 2010a). Usually, sales decrease up to 80% after patent
expiry, mainly due to substitution by cheaper generics3 (Basu, 2010a). As a result,
todays new pharmaceutical products must generate more money in less available time.
Additionally, there is increasing pressure on drug prices by governments. This calls for
stable and efficient manufacturing processes right from commercial launch in order to
avoid inefficient and thus excessive manufacturing costs.
Many industries have designed concepts and methods to make the development process
more efficient and thereby shortening it (Yeh et al., 2008; Tessarolo, 2007; Boyle et al.,
2006; Koufteros et al., 2005; Gerwin and Barrowman, 2002; Palacios and Gonzlez,
2002). Due to the highly regulated development process in the pharmaceutical industry,
established approaches to integrated development from other industries cannot be used
without adaptations. In the pharmaceutical industry, new products are tested for efficacy
and safety in multiple clinical studies. If results are accepted by regulatory authorities, a
product is approved for sale. However, the commercial manufacturing process must be
identical to the process used during development and especially during production of
material used in late studies. Otherwise, there will have to be additional studies, resulting
in increased development costs and time (FDA, 2004). The transfer of the production
Generics main advantage are the lower production costs. There are three reasons for these: (1) Production was
already optimized for some years when the product was still patent protected. (2) There is a high potential of
production optimization at researching companies. For generics producers production is the central driver of
success, while traditional pharmaceutical companies consider production to be less important (Basu, 2010a). In
US pharmaceutical companies, losses due to inefficient processes are estimated to be as high as 50bn USD (Basu,
2010a; Macher and Nickerson, 2006). (3) Generics producers do not have to finance a large R&D driven
overhead. They usually only have a small development department dealing with the adaptation of products and
processes to the company and its equipment.
Introduction
1.00
Launch Site
Site not dedicated
to product launches
0.75
0.50
0.25
0.00
0
As literature and case studies suggest, there is one specific method to avoid the issues
described above: integrated development with a special focus on cross-functional teams
(Tessarolo, 2007; Koufteros et al., 2002, 2005; Yeh et al., 2008; Boyle et al., 2006;
McDonough, 2000). Central to this concept is the early integration of production during
development. This allows ensuring in an early phase that the developed processes can be
efficiently implemented in a commercial scale and with commercial-scale equipment.
Data from practical examples demonstrate that stronger collaboration of development
and production in companies leads to more efficient processes (Figure 6). The more
advanced a company becomes in integrated development, the earlier processes are
adapted and optimized to the commercial scale environment. Ideally, the processes
transferred into commercial production do not need any further optimization and do not
Data taken from unpublished Operational Excellence (OPEX) in the Pharmaceutical Industry Benchmarking
2004-2012 (Chair of Production Management, Institute of Technology Management, University of St.Gallen).
Manufacturing process efficiency is calculated as product of Yield (%), Rejected Batches (%), Overall OEE (%),
and Deviations (%). Production involvement during development is based on the question "Manufacturing
engineers (e.g. Industrial engineers) are involved to a great extent in the development of new drug formulation
and the development of the necessary production processes", assessed by a 5-point-Likert scale. All data is based
on information of 91 participating pharmaceutical companies.
Introduction
The term pharmaceutical industry is equal to the Life Sciences industry, covering both the pharmaceutical and the
biotechnological industry. Although there are some differences between these industries (e.g. different
manufacturing principles, different regulatory requirements, different manufacturing scales, etc.), they share main
characteristics and are thus considered as one industry.
In this dissertation, the following industries are covered by the term highly regulated industries: the
pharmaceutical, the biotechnological, to some extent the chemical, to some extent the food, the aerospace, and the
atomic industry. They all share the fact that deficiencies in their products can cause massive damages to the
consumer. They have to fulfill highest (safety-)requirements. Generally, they (mainly the production facilities) are
inspected regularly by regulatory authorities. Furthermore, highest risks are common to all these industries. Thus,
final products cannot be improved by experiments but rather have to be fully functional and safe even for the first
prototype (e.g. when building a nuclear power plant, all potential errors must be identified and eliminated during
design and development phase in order to avoid massive damages). To substitute tests under real conditions,
simulations and models are often used by these industries.
Introduction
alone is not enough reason to not be able to adopt concepts from other industries without
major adaptations, especially since there are some examples from highly regulated
industries (mainly aerospace industry) (Basu, 2010b; Araujo and da Cruz, 2000; Mendes
et al., 2002; Terwiesch and Loch, 1999). It is rather the combination of high regulation,
highest safety and quality standards, and the somehow to other industries not comparable
development process that makes the pharmaceutical industry special and thus requires a
different approach and major adaptations to established concepts.
In the pharmaceutical industry production facilities and processes are regularly inspected
by regulatory authorities7. They define, control, and enforce new standards and
guidelines. In some markets it is only possible to sell products from certified production
sites (e.g. in the US it is only possible to sell products that were produced in FDAcertified production sites). The reasons for high regulation are highest quality, cleanness,
and safety requirements in order to meet patient safety. Regulatory agencies validate
both production equipment and processes.
The most relevant regulatory authorities (also for this dissertation) are USAs Food and Drug Administration
(FDA), Europes European Medicines Agency (EMA), and Switzerlands Swissmedic.
Introduction
Development Process
Discovery
Early Development
Research
Late Development
Pre-Clinical Development
Clinical Development
Registration
Launch
Lead
Identification
Candidate Selection /
First Toxicity Dose
In Vitro Models
Animal Models
Phase I
Phase II
First Efficacy
Dose /
First Patient Dose
Phase III
Product Decision
Registration
First Submission
Global Launch
First Launch
First Approval
Development begins with the identification of leads8 that are further optimized. The most
promising lead becomes a so called development candidate. During early development, it
is pre-clinically tested in a lab environment and later in animal models. Then three
clinical phases follow, where tests in humans are conducted in order to test the safety
and efficacy as well as to gain more knowledge about the drug.
The term lead describes a chemical or biological molecule to which a clinical effect is attributed (at least in
theory).
Introduction
Clinical phase II
Clinical phase IV
~1 year
1-2 years
1-3 years
open
few healthy
humans
few hundred
target patients
several hundreds
to thousands
target patients
study-dependent
Study duration:
Study
participants:
Clinical phase I studies are usually conducted in a small number of healthy humans.
They are typically used to assess ADME (absorption, distribution, metabolism, and
excretion) attributes, meaning to gain knowledge about how the substance behaves in the
human body, as well as tolerance data in order to plan patient dosing in phase II studies.
Clinical phase II studies are typically conducted in a few hundred patients. The goal is to
test efficacy of the drug and demonstrate its clinical effect (Proof-of-Concept, PoC).
They are also used to gain further knowledge on dosages.
Clinical phase III studies are usually studies involving a large number of target patients
(several hundreds to thousands). The goal is to demonstrate safety and efficacy for
registration. In general, at least two adequate studies are required by regulatory agencies
for the approval of a new drug. Phase III studies can also be conducted in order to
develop new therapeutic indications.
Clinical phase IV studies are post-approval studies. Usually they are used to gain
extended data about the product and its mechanisms in order to allow for more specific
and optimal treatment.
During the three clinical phases many development projects are terminated mainly
because they do not meet the requirements and thus constitute a risk or fail to have the
desired effect. In total, it is believed that only about 1% of all drug candidates master the
path from pre-clinical development to a final product (PhRMA, 2010). As soon as
10
Introduction
enough data about safety and efficacy is collected, usually during or at the end of clinical
phase III, the drug product is filed for submission with the regulatory agencies. It also
has to be specified where and how it was and will be produced. Thus a detailed
manufacturing process is submitted and ideally also approved.
Parallel to clinical development, the product is technically developed as well. During the
clinical phase I mainly the formulation and basic manufacturing processes are developed.
During phase II, the manufacturing process is developed in small scale environment (lab
scale) and subsequently scaled-up to large scale. During technology transfer before or at
the beginning of phase III it is finally transferred from development to production. It is
often only rudimentarily adapted to work in commercial scale with commercial
equipment and to produce enough product and data to register with regulatory agencies.
Since this is a sub-optimal process, global launch manufacturing problems often arise
and lead to massive delays. In this phase launch sites have an important role, as they
serve to adapt manufacturing processes to commercial scale in a trial-and-error
procedure. Major changes in the approved process entail subsequent filings and imply
further delays.9 If the process is not adapted, it is produced with an inefficient
manufacturing process in routine production. This inevitably leads to increased
manufacturing costs.
As Basu (2010b) appropriately remarks, "If process development is largely empirical in
nature, then manufacturing becomes a 'Big Experiment' and learning on the plant floor
can be very expensive" (Basu, 2010b, p.30).
Any changes to the product and the manufacturing process must be documented and filed with regulatory
authorities. If major changes influence product quality or efficacy, a clinical study (with only few participants)
has to be conducted in order to show that the product is equivalent to first approval.
Introduction
11
Its main goal is to induce a shift from the currently prevailing Quality after Design10.
Regarding process development and quality, a shift from current re-active methods to a
pro-active thinking is to be achieved. Primarily the initiative should improve quality of
pharmaceutical products, mainly by defining the manufacturing process qualityfriendly and by identifying those production steps that could cause quality issues early
during development. These steps can then be closely monitored during production.
Insufficient quality can thus be identified right at the occurrence and be corrected this
leads to less scrap. The application of QbD improves the understanding of the product
and especially of the process.11
As a benefit of applying QbD companies are offered a simplified process of registration
by the FDA. Furthermore, QbD should reduce development time and along with that
development costs decrease as well. Additionally, production costs can be reduced with
a consequent application of QbD. As of the definition of QbD, production should be
involved early when defining the production process in development so that process
scale-up runs simplified and prepared and processes transferred to production can be
implemented and applied in an efficient way (Yu, 2008). Further benefits from QbD
application include: Reduced costs of quality, shortened process development time,
increased flexibility for process adaptations or changes, and reduced efforts for
regulatory authorities (McCormick, 2006; Tozer, 2008).
Full QbD implementation might have a major drawback. QbD is FDA-driven and
adopted by many other regulatory authorities. Some, however, still accept solely
classic registration. If a company intends to serve different markets of which some
regulatory authorities accept QbD registrations and others do not, it has to prepare two
major different registration dossiers. This might also be a reason why some companies
follow QbD approaches internally, but still register their products in the classical way.
In many companies QbD is not fully implemented and can thus not unfold its full
potential (Basu, 2010b; Rathore, 2010). Reasons therefor are identified quickly: (1) The
10
Quality after Design means products are inspected for quality after production. This can lead to excess amounts
of scrap. Current efforts such as Lean Six Sigma, RFT (Right the First Time), OPEX (Operational Excellence),
etc. aim to monitor product quality after product launch and eventually to improve it through production
optimizations (Basu, 2010a).
11
Thorough knowledge of manufacturing processes improves production as well. Efforts like Lean Six Sigma
(among others) to optimize production are rather short-term measures because no real process understanding is
built up (Basu, 2010a).
12
Introduction
QbD Process
TPP
TPQP
CQA
Process
Design
CPPs /
CMAs
process definition
(to achieve
quality)
identification of
critical process
steps
(to achieve
quality)
Design
Space
Production
TPP: Target Product Profile; TPQP: Target Product Quality Profile; CQA: Critical Quality Attributes; Process
Design; CPPs: Critical Process Parameters; CMAs: Critical Material Attributes.
Introduction
13
Thereafter, the Manufacturing Process is defined. During this step it is important that
production is already involved and assists to shape the manufacturing process in a most
realistic and practical way. Specialists from launch sites or Transfer Organizations are
most likely to possess the most expertise and experience therefor. Based on CQA, those
Critical Process Parameters (CPP) and Critical Material Attributes (CMA) are
identified, which have a direct or indirect influence on product quality. These parameters
and attributes have to be monitored continuously in commercial production in order to
control product quality.
All this preparatory work leads to the definition of the Design Space. There are many
differing definitions of the term design space. Generally and especially in the context
of QbD, it is defined as definition of all processes and parameters and their ranges and
critical margins.13 These ranges and margins are identified and set by experiments,
calculation models, and preliminary built-up knowledge. The design space directly
influences manufacturing of the final product and the monitoring of the identified
process parameters.
However, it has been found to be a problem that the manufacturing process is mainly
designed by development rather than by production. This implies that the process is
defined for a small scale rather than for large commercial scale. These differently scaled
processes can differ significantly, what also affects CPP and CMA and thus also the
design space. If commercial manufacturing is started with the design space for lab scale,
usually major adaptations are necessary. The challenge is involving production in
process development. Thereby, scale-up occurs at an early stage in development and
leads to a scale-adapted design space and thus to a smooth product launch with efficient
manufacturing processes. This involvement is only possible if experts from launch sites
can share their knowledge and make it accessible to development specialists. This can be
achieved by integrated development approaches (especially cross-functional teams).
Ranges for specific parameters defined in the design space are a distinct advantage of
QbD. In traditional pharmaceutical production, validated manufacturing processes
cannot be changed without regulatory effort. For products approved within QbD, the
13
A descriptive example: For a certain process step the pH value is identified to be a CPP. For example, it has to be
13. Through experiments, prior acquired data and knowledge, and scientific methods it is shown that the process
step also works at a pH value between 12 and 14 with no difference in the results. In the design space the pH
value is defined as within the range of 12-14 to produce the desired quality.
14
Introduction
processes can be changed as long as it can be shown that the critical parameters stay
within defined ranges. QbD brings a lot of flexibility in commercial production and
effectively reduces administrative and regulatory effort for process adaptations.
Contrary to theory, a detailed and practical implementation model for QbD is missing.
Such a model would show how to efficiently implement QbD in practice and what the
emerging consequences could be. This dissertation contributes to understand the
interaction between development and production as well as the influence of launch sites
and Transfer Organizations. Further it shows how these insights can be introduced into
QbD.
One consequence of the science driven QbD approach is occurring in technical
development: There is a shift, mainly driven by regulatory agencies, away from
inflexible phases in technical development towards a more continuous approach (FDA,
2011). Late process development is called process design phase and used to deliver a
scientific rationale of why the product is how it is. Following used to be technology
transfer and validation, now called process performance qualification. In the end is
continuous process verification, meaning a continuous monitoring of the process and the
product quality. This is more aligned with ongoing QbD efforts, meaning to use a
scientific approach instead of trial-and-error. However, it is still in a rebuilding phase
and its full effects are yet to be harvested.
Introduction
15
16
Introduction
proceeding. Fifth, industry and case study insights transferred the reference framework
into a descriptive reference model for the pharmaceutical industry.
Only pharmaceutical companies being globally active and having multiple sites were
considered to be part of the research process. There were no other restrictions, however,
these criteria proved to be enough to obtain a quite homologous group of companies.
This is mainly to ensure that companies and their challenges but also developed and
proposed solutions are applicable to all participants and research results can be
generalized.
Reference framework
Validation
Literature review
Reference framework
Industry survey
Case studies
Introduction
17
18
Introduction
2007). However, simply having advantageous resources at hand may not suffice for
competitive advantage: distinctive capabilities related to the use of resources are needed
(Penrose, 1959).
A clear definition of RBV terminology (e.g. what resources are) is missing (Thomas and
Pollock, 1999). It is suggested that the identification of V.R.I.N. resources responsible
for competitive advantage is achieved by finding superior performance and then
connecting it to unique resources the firm appears to possess (Eisenhardt and Martin,
2000; Barney, 1991). Thus, the definition of the RBV theory is tautological (Wang and
Ahmed, 2007).
The business environment grew more dynamic. This challenged classic RBV
propositions: they were found to be static and not considering the influence of markets
dynamics (Eisenhardt and Martin, 2000; Priem and Butler, 2001). This led to the
creation of dynamic capabilities, combining both resources and dynamically to the
environment adapting capabilities, as an enhancement to the RBV (Teece et al., 1997;
Helfat, 1997; Eisenhardt and Martin, 2000; Zahra and George, 2002).
Dynamic capabilities are defined as the firms processes that use resources
specifically the processes to integrate, reconfigure, gain and release resources to match
and even create market change, and the organizational and strategic routines by which
firms achieve new resources and configurations as markets emerge, collide, split, evolve,
and die (Eisenhardt and Martin, 2000, p.1107). They are a firms behavioral
orientation to constantly integrate, reconfigure, renew and recreate its resources and
capabilities, and most importantly, upgrade and reconstruct its core capabilities in
response to the changing environment to attain and sustain competitive advantage
(Wang and Ahmed, 2007, p.34). Thus they are not processes, but rather embedded in
processes (Wang and Ahmed, 2007, p.34).
Like in the RBV, terminology is not definite: for example, dynamic capabilities are
defined as the firms ability to integrate, build, and reconfigure internal and external
competences to address rapidly changing environments. Dynamic capabilities thus
reflect an organizations ability to achieve new and innovative forms of competitive
advantage given path dependencies and market positions (Teece et al., 1997, p.516).
This is very similar to the definition of capabilities in RBV: The key role of strategic
management in appropriately adapting, integrating, and reconfiguring internal and
Introduction
19
1.5.3 Structure
This dissertation is structured in 7 chapters with the following content (Figure 10):
1.5.3.1 Chapter 1: Introduction
The first chapter describes the personal motivation for the research as well as the
theoretical and practical relevance. Important terms and concepts are introduced.
Furthermore, the research goal, question, design, and theory are defined.
1.5.3.2 Chapter 2: Theoretical Foundation
In chapter 2 insights from literature and theoretical basics are discussed. The focus
mainly lies on cross-functional collaboration, which is the most important aspect of
integrated development. Implications from the theoretical basis constitute the conceptual
framework.
20
Introduction
Chapter 1: Introduction
1.1 Motivation
2.4 CrossFunctional
Teams
6.3 Conclusion
Introduction
21
2 Theoretical Foundation
This chapter builds the theoretical base of the research by reviewing the up-to-date
literature. The literature was screened for existing information to the topic of integrated
development in general and to some of its methods in particular. Therefore, the literature
about integrated product development, concurrent engineering, cross-functional teams,
and success factors was reviewed. The literature on integrated development discusses its
role in development performance and describes supporting tools and methods. The
outcomes of this literature review provide the elementary input for the reference
framework.
24
Theoretical Foundation
Product quality: it describes the quality of the finished and marketed product.
Manufacturing costs: they describe all costs that are incurred to manufacture the
product. They are also influenced during development: if the manufacturing
process is developed to be effective and efficient, no adaptations are required
(which means no additional costs). Furthermore, inefficient processes result in
excessive manufacturing costs.
In order to address the development of new products in a systematic way, a structured
process was defined: the New Product Development (NPD) process14 (Krger et al.,
2010). This approach is considered to be the paradigm of new product development
(Krger et al., 2010; Gerwin and Barrowman, 2002). The NPD process is a sequence of
different steps, activities, and decisions during the development of a new product from
the initial idea to the commercial manufacturing of the final product (Yeh et al., 2008;
Cooper and Kleinschmidt, 1997). Figure 11 depicts the NPD process used in this work.
NPD Process
Customer
requirements
Development
proposal
Project
planning
Conceptual
design
Product
design
Prototype &
test
Process
development &
pilot run
Manufacturing
Customer
Figure 11: The NPD-process according to Yeh et al. (Yeh et al., 2008, p.138)
Cooper & Edgett (2003) demonstrated that the success rate of development projects
following the NPD process lies at around 60%. Traditional NPD processes are followed
sequentially, they are not overlapping or integrated (Gerwin and Barrowman, 2002).
Thus, no activities and process steps are executed in parallel. In order to render the
process more efficient it is proposed avoiding wastage of resources on peripheral
activities, changes, and reworks (Yeh et al., 2008, p.132). This means generally the
prevention of unnecessary activities (Palacios and Gonzlez, 2002). Furthermore, it was
14
There is not one single NPD process, there are rather various different variants described. They do not
significantly differ in contents and goals, but rather in their general definition and along with that in the number of
defined steps. Among others there are variants with four (Sun and Wing, 2005), seven (Yeh et al., 2008), eight
(Nijssen and Frambach, 2000), or a variable number (Thia et al., 2005) of steps. Furthermore, these approaches
differ in their extent of formality. An example of a very formal NPD process is the Stage-Gate NPD process
(Cooper and Edgett, 2003). In this dissertation, the term NPD process refers to the definition by Yeh et al. (Yeh et
al., 2008, p.135f).
Theoretical Foundation
25
searched for influence factors responsible for shortening the development time. The
following factors (among others) were identified and further researched for their
influence: modularity at product structure level (common basis for an entire product
family) (Danese and Filippini, 2010), product vision (common vision and idea about a
product in project teams) (Tessarolo, 2007), and integration15 (Tessarolo, 2007; Ettlie,
1995). It was demonstrated, that under certain conditions they all have a positive effect
on NPD process performance. Thus they lead to better manufacturing processes (higher
manufacturability) while shortening the development time.
Furthermore, different tools, methods, and practices with positive effects on NPD
processes were identified (Palacios and Gonzlez, 2002). In different studies it was
shown that the consequent and consistent application of one or more such tools increase
NPD process success significantly (Yeh et al., 2008; Thia et al., 2005; Gonzlez and
Palacios, 2002). Despite these obvious benefits, they are applied only to a small extent in
development, particularly compared to production (where such tools are applied
regularly and with great success) (Yeh et al., 2008). Various reasons therefore were
identified: low level of awareness among project managers, limited faith of managers
on the effectiveness of NPD tools, rejection of change due to culture (Thia et al.,
2005, p.407) as well as the fact that R&D engineers are often not familiar with the tools
and do not know when in the development process to apply them (Yeh et al., 2008).
15
Generally, the strategy of integration is considered to be the key to NPD success (Koufteros et al., 2005). For the
highest possible effect, integration should start the earliest possible. It can be divided in internal and external
integration. While internal integration includes concepts like cross-functional teams, concurrent engineering, and
early involvement of all relevant organizational units, external integration is subdivided into customer and
supplier integration. Customer integration describes the co-operation of the developing company with its
customers. This ensures that customer requirements are considered and development is focused on them
(Koufteros et al., 2005). Supplier integration is again subdivided in product or black box integration (suppliers
develop parts for the final product on their own) and process or grey box integration (collaborative development
in order that supplier processes can be integrated in the final design) (Koufteros et al., 2005).
26
Theoretical Foundation
concurrent workflow (Naveh, 2005, p.2791). The generic IPD process consists of the
following four phases: detailed task definition, conception, detailed development work,
and prototype design (Krger et al., 2010). The most important characteristics are the
degree of overlapping and interaction of NPD activities (Gerwin and Barrowman, 2002).
The following is typical for IPD concepts and is most often applied to achieve IPD:
cross-functional NPD teams (CFT) and concurrent product development processes
(CDP) (Boyle et al., 2006, p.38); cross-functional and interdisciplinary teams (Griffin,
1997b; McDonough, 2000); overlapping of certain activities during the development
process, leading to a partial or complete parallel execution, as well as interdisciplinary
teams (Krger et al., 2010; Gerwin and Barrowman, 2002); a very holistic product
consideration, teamwork, customer orientation, information and communication flow,
the application of new technologies, and the dynamic work flow (Krger et al., 2010);
concurrent
engineering,
design
for
manufacturability,
early
manufacturing
involvement (Gerwin and Barrowman, 2002, p.939). Among others, creating more
manufacturable design has many advantages compared to other approaches (for
example the simpler NPD approach) and is responsible for its growing popularity
(Gerwin and Barrowman, 2002, p.938).
The most frequently mentioned cross-functional or interdisciplinary teams and
concurrent engineering are administrative methods that increase efficiency of IPD
compared to NPD (Boyle et al., 2006). However, they can be accompanied by critical
aspects, for example burn out of team members and too many meetings (Krger et al.,
2010; Gerwin and Barrowman, 2002). These two and their consequences are main
reasons why the implementation of the IPD process requires a high degree of
coordination (Gerwin and Barrowman, 2002). For the same reason, commitment of top
management (Boyle et al., 2006; Swink, 2000) and the willingness of different functional
units to collaborate (Boyle et al., 2006) are critical for the success of IPD projects.
There exist further more practical and technical tools and techniques (for example QFD,
FMEA, Fishbone, and others) with the goal of improving the IPD process. They can be
divided in three areas: organizational design approach, information-processing
approach, and application of total quality management principle (Gerwin and
Barrowman, 2002, p.939). Both Boyle et al. (2006) and Yeh et al. (2008) provide an
overview of the most frequently used tools and methods. Yeh et al. (2008) further
provides an evaluation of the usage frequency during the NPD process steps as well as
Theoretical Foundation
27
the influence of the tools and techniques.16 The performance of development projects
following IPD principles can be measured by development time, development cost,
product quality, and overall product performance (Gerwin and Barrowman, 2002,
p.940). These indicators as well as the achieving of their set goals are all inter-connected
and depending on each other.
By the consistent implementation of many IPD principles and the application of various
tools and techniques, Toyota managed to shorten the development time of new car
models by two to three years (Naveh, 2005). Gerwin & Barrowman (2002) provide a
general overview of companies that have so far been analyzed for their implementation
of the IPD process.
Due to their effectiveness in the IPD process17 on the one hand and because of their
administrative and organizational nature on the other hand, the following concepts of the
IPD approach are discussed in more detail (Yeh et al., 2008): Cross-functional
(interdisciplinary) teams and concurrent engineering. They both are similar to parts of
QbD and therefore highly relevant. They are connected to higher manufacturability,
which consists of the ability to manufacture a product as well as of the efficient adoption
(without adaptations) of developed manufacturing processes. Furthermore it was shown,
that especially cross-functional teams are very common in development of investigated
companies (Yeh et al., 2008).
16
The usage frequency (table 6) was assessed at 88 different high-tech companies from Taiwan (Yeh et al., 2008,
p.141f). Derived from that is the influence on the overall performance of the IPD process (Table 7) (Yeh et al.,
2008, p.145f).
17
The table (table 5) provides an overview of tools and techniques used for increasing efficiency during the IPD
process (Yeh et al., 2008, p.140). Most of them are more of a technical nature and aim to simplify the
development engineers work. Only very few are related to organizational topics.
28
Theoretical Foundation
marketing) (Kamrani and Vijayan, 2006). The degree of this involvement can be
measured indirectly by the product design quality manufacturability (Doll et al., 2010;
Swink, 1999). It is an indicator for the degree of fit between product design
specifications and capabilities of the manufacturing process (Adler, 1995) and thus also
indirectly to which extent the production is involved in the development of new
products. Early involvement of other organizational units gives participants the ability to
participate before decisions are taken (Koufteros et al., 2005). Additionally, information
is distributed to all participants (Koufteros et al., 2005). Thus, erroneous developments,
developments heading in the wrong direction, and double work due to missing
information coordination can be prevented and time and costs can be saved. The
involvement also increases communication and thus reduces uncertainty among team
members (Koufteros et al., 2005). Concurrent engineering is using more and more IT
tools and methods. By this it is ensured that generated knowledge and know-how is
available and can be accessed during future projects, which in turn can again shorten the
development time (Kamrani and Vijayan, 2006).
Theoretical Foundation
29
All involved organizational units usually have their own orientations, cultures, and
languages. In cross-functional teams they all come together and must be managed. For
successful and productive collaboration in cross-functional teams some team
characteristics were identified (McDonough, 2000):
Goals and visions define boundaries for the team in order to prevent it from
constantly re-defining itself and its tasks.
Team autonomy enables the team to take decisions on its own.
A general climate supporting cross-functional collaboration is needed.
Furthermore, a climate of importance and urgency of the project leads to
constructive pressure.
The ideal team mix must be chosen to combine many different skills. By this,
different inputs can be processed in a most reasonable way. Functional diversity
helps project team members to understand the design process more quickly and
fully from a variety of perspective, and thus it improves design process
performance. Moreover, the increased information helps the team to catch
downstream problems such as manufacturing difficulties or market mismatches
before they happen, when these problems are generally smaller and easier to fix
(Brown and Eisenhardt, 1995, p.367).
Strong team leadership enables the team. Furthermore, it provides directions for
the team members without hindering them to work freely.
Top management support should be visible by commitment to the project and
the team. Top management should mainly be helping in the case of problems, it
should encourage the team and be making things happen (McDonough, 2000,
p.225f).
Champions are individual team members that are indirectly valuable for the
team. They can be distinguish by special efforts in certain project steps or
processes and thus help to significantly advance the project.
Cooperation between involved organizational and functional units facilitates the
project flow.
Commitment of all team members is crucial for project success because it leads
to common efforts in a common direction.
Each team member must be willing to contribute to the overall project success.
Respect, trust, and honesty between all team members promote the team culture.
30
Theoretical Foundation
18
Sh
a
r
e
vis d, c o
ion
m
m
,
s
upp on, a
Or
nd
or
ga
t
(cr niz ati ed by unifie
oss
on
d
se
n
f
i
unc al cli
or goals
ma
Te
tio mat
am
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n
e
a
a
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tea uppo
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ent
m
c
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a
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of
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o
ard
xim
To
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or
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ma
am
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lea
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sh
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p
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rol
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&
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itm
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o
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i
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r
ans
fer
p
r oc
ess
Theoretical Foundation
31
(De Clercq et al., 2011; Hirunyawipada et al., 2010; Nakata and Im, 2010; Barczak et al., 2009; Edmondson and
Nembhard, 2009; Emery, 2009; Hyung-Jin Park et al., 2009; Sarin and OConnor, 2009; Hafer and Gresham,
2008; Kim and Kang, 2008; Appelbaum and Gonzalo, 2007; Cooper and Kleinschmidt, 2007; Sarin and
McDermott, 2003; Sethi et al., 2001; Holland et al., 2000; McDonough, 2000; Song et al., 1997; Denison et al.,
1996; Pinto et al., 1993)
32
Theoretical Foundation
Theoretical Foundation
33
No. of
companies
186
205
Sports equipment
88
High-tech firms
Tessarolo, 2007
154
269
244
Naveh, 2005
Hi-tech electronics
25
57
McDonough, 2000
112
136
US manufacturing industry
57
95
High-tech
102
Electronic firms
200
289
Griffin, 1997a
21
21 divisions of 11 firms
79
44
Electronic firms
36
Computer firms
103
21 chemical firms
62
20
Auto firms
83
Chip firms
547
Schoonhoven,
Lyman, 1990
Eisenhardt,
&
34
In summary, the following insights and consequences for this research can be drawn:
New
Product
Development
concepts
are
widely
applied
and
their
In chapter 3 all aspects from literature reviewed in chapter 2 are put together and
transformed into a reference framework. First, the framework is introduced in general.
This is followed by detailed descriptions of all components as well as the effect on
performance.
The reference framework is used to guide all research relevant for this dissertation. The
following industry survey and case studies are based on this framework.
36
successful integrated development. They all have different characteristics and effects on
development performance. In combination they form an effective framework for
integrated development in the pharmaceutical industry. All topics are discussed in detail
in the next section.
37
38
process in order to represent the respective involvement and roles. However, it is crucial
to not only include those with direct contributions, but also those, whose interests
become requirements later in the process.
The team composition varies during the development process. Along a generic
development process, it is defined which organizational unit or function contributes to a
process step in what function, to what extent, and in collaboration with whom. Figure 13
shows a fictional idealized form of contribution and collaboration along the development
process. It is obvious, that contribution of early functions decrease over time while it
increases for late functions. However, in an ideal setting, most functions are to some
extent involved in all development steps.
Early Process
Final
Development
Formulation
(lab scale,
Development
feasibility)
Pilot Scale
Full Scale
Technology
Transfer
Validation
Registration
Launch
Post-Launch
Improvements/
Changes &
Maintenance
Early Stage
Development
Late Stage
Development
Transfer
Organization
Launch Site
Commercial
Production
39
covered by team behavior factors (Table 6). They describe how collaboration in teams
can be most effective.
Enabler
Top management support
Team leadership
Formal process
Clear roles & responsibilities
Resources / mix
Formal knowledge transfer process
Context
Shared, common, and unified goals
and vision, supported by senior
management
Organizational climate supportive
of (cross-functional) teams
Team co-location / proximity
Team reward
Team behavior
Commitment
Creativity
Communication / interaction
Trust & respect
Autonomy
Informal interpersonal
relationship / social cohesion
Cross-team coordination
Performance
Figure 14: Categorized success factors from literature, showing the interrelationship and the
effect on performance.
The following tables list all success factors as well as their detailed characteristics and
impact on performance as they are used in this reference framework (Table 4, Table 5,
Table 6).
Teams are rewarded for their performance as More team work and acting in the sense of the
team rather than as individuals. Furthermore, overall project outcome leads to better project
teams are rewarded according to overall project performance.
success.
Team reward
Impact on Performance
Actions and contributions are taken in a way
that the overall project benefits. Thus less rework is needed and project execution is sped
up.
Characteristics
Shared, common, and unified goals and vision, Overall goals are set for development projects.
supports by senior management
This ensures that all team members, even when
only contributing at certain phases, have not
only their own contributions success in mind,
but rather overall projects success.
Success Factor
40
Development of a Reference Framework
Team leadership
Formal process
Resources / mix
Impact on Performance
Characteristics
Success Factor
Characteristics
All team members are highly committed to
the team and its actions and decisions.
Team members are encouraged to work
creatively rather than following a
standardized and formal path.
Communication and interaction between
team members is occurring rather than
members work for themselves individually.
Furthermore, all team members are informed
of all actions taken in the team.
Team members trust and respect each other.
Success Factor
Commitment
Creativity
Communication / interaction
Autonomy
Cross-team coordination
Impact on Performance
42
Development of a Reference Framework
43
3.2.3 Organization
The organization in place during the development process has crucial influence on its
outcome. It mainly determines success and outcome of cross-functional collaboration.
Early and late stage development (responsible for process development) are both part of
the development organization. The responsible launch site belongs to production, but it
is separate from but affiliated with routine production. It maintains close connections
with development in order to exchange knowledge. Organizationally between
development and production is a so called Transfer Organization: it is a team or
organization mainly responsible for the transfer from development to production.
Compared to traditional launch sites, a Transfer Organization is part of production but is
not affiliated with routine production. Thus it is more closely connected to development.
During its time of involvement in the development process, the Transfer Organization
represents productions interest. Both the launch site and the Transfer Organization can
also be one combined function instead of two separated ones.
This chapter describes the empirical investigation that was undertaken in order to
evaluate the reference framework. First, it is described how the survey was set up and
how it was conducted. Second, the general results of the survey are outlined. Third, some
special aspects identified during the survey are explained. Finally, general findings and
insights are summarized.
Figure 15: Adapted reference framework used for the industry survey.
46
They only differ in the medium used: one was sent out as PDF document created with
TeleForm19 while the other was implemented in an online survey tool20. The PDF-based
questionnaire used for the survey is depicted in the appendix.
Section A: In this general section data about the participants company, function,
department, location, and work experience was gathered.
Section B: This section contained questions about the participants company: size
(number of employees), amount of employees in development and production (both
percentages), revenue and percentage of R&D expenditures for the years 2009, 2010,
and 2011, number of CMC development and manufacturing sites worldwide, and fields
it operates in (branded drugs / innovator, generics, OTC, biotech, or other).
Additionally, the average overall development costs and times were determined.
Section C: This section contained four questions about the perceived effect and benefit
of integrated development. Also, one question assessed the participants companys
degree of working in an integrated way during development projects.
Section D: This section contained questions about the organizational set-up of the
participants company or department: way of working in development teams,
organizational unit responsible for process development, existence and organizational
affiliation of a transfer group, existence and number of launch sites, existence and
organizational affiliation of launch groups, similarity of equipment at pilot and launch
sites, process development groups capability and equipment knowledge of first and
secondary manufacturing sites. Additionally, the composition of CMC teams was
determined.
Section E: It contained questions about tools used during development, mostly related to
QbD: to what extent a shared knowledge management solution, minimum QbD elements,
DoE, and PAT are used during pilot scale, full scale, technology transfer, launch, and
routine production. Further the reasons for minimum QbD, DoE, and PAT application
were requested.
Section F: This section consisted of a RACI-matrix in which the degree of involvement
of selected member groups of cross-functional teams along the previously described
19
20
47
pharmaceutical development process (Figure 21) was entered. Further elements assessed
include: a rating of the transfer between process steps, the duration of each process steps
(in months), the average amount of work hours for each process steps (for development
and production staff), the average amount of employees working on each process step
(for development and production staff). Also, it was asked when (clinical) POC, start of
clinical phase III, and final decision on first manufacturing site occurred. An additional
field allowed providing comments about the RACI-matrix.
Section G: In this section 13 statements, each representing one of the previously
described common success factors of cross-functional collaboration identified in
literature, were rated on a 5-point Likert-scale (from strongly disagree to strongly
agree). Additionally, there was an open text field to add further success factors;
however, it was not used by any of the participants.
Section H: The last section was about metrics. First, it was asked how many active
development projects currently were in certain clinical phases (clinical phase I, clinical
phase IIa, clinical phase IIb, clinical phase III, and launch). It was then rated whether
time, cost, and quality objectives of pilot scale development, full scale development,
technology transfer, product launch, and manufacturing process efficiency of all
products launched during the last five years were met. The rating was based on a 5-point
Likert-scale (objectives not met to objectives completely met). The second question
was about how many process adaptations and process changes (post-approval changes,
have to be filed at regulatory authorities) occurred on average if all products launched
during the last five years were considered. Again, a 5-point Likert-scale (none, very
few (1 in 10 launches), few (1 in 5 launches), some (1 in 3 launches), many (1 or
more in each launch)) was used for the rating. Also, it was asked whether there had
been an improvement regarding process development compared to ten years ago. It also
contained an open text field to enter any additional data, which, as expected, was used
only were rarely.
48
49
others
8%
Quality
6%
Development
62%
Regulatory
0%
Production
24%
Austria
5%
Italy
5%
Israel
3%
India
5%
n/a
5%
Switzerland
22%
Germany
22%
Netherlands
6%
USA
27%
up to 250
34%
over 20,000
32%
251-1,000
3%
5,001-20,000
14%
1,001-5,000
17%
other
10%
Branded Drugs /
Innovator
33%
Generics
14%
Biotech
31%
OTC
12%
50
>6 years
5-6 years
3-4
1-2 years
<1 year
0
10
12
14
The sample contained all different kinds of companies: from small, rather local up to
large international companies, as well as from highly specialized to very broadly
operating companies. Also in terms of geographical distribution, most major markets
(North America, Europe, and India) were represented. Additionally, there were
participants from different departments and functions (e.g. development, production,
etc.) and with different level of experience. All in all this sample is a good representation
of todays companies of the pharmaceutical industry and can therefore be used to derive
general statements about todays state of the industry regarding integrated development.
51
manufacturing process efficiency (in routine production). In order to get a more detailed
picture, these objectives were further divided into time, cost, and quality objectives and
assessed separately.
Early Process
Final
Development
Formulation
(lab scale,
Development
feasibility)
Pilot Scale
Full Scale
Technology
Transfer
Validation
Registration
Launch
Post-Launch
Improvements/
Changes &
Maintenance
For each analyzed process step a general performance-index (PIi) was generated, as
shown in equation (1). It was decided to apply different weights to time (T), cost (C),
and quality (Q):
Quality standards are very high in pharmaceutical companies and have to be maintained
at such a level. Therefore, the industry is very well adapted to providing high quality.
The quality part of objectives was thus only weighed wQ=0.3.
Time is a very important factor in product development. However, timelines are
influenced by clinical development activities (e.g., clinical trials). Only in the case of
early clinical success, time also gains importance in technical development. Accordingly,
the time part of objectives was weighed wT=0.6.
Despite the fact that the main part of development costs is determined by clinical trials,
the industry is also very cost-sensitive when it comes to technical development. Costrelated objectives were mentioned to be the most important by all industry
representatives and therefore weighed wC=1.0.
)+( )+(
+
+
(1)
The performance-indices of all five process steps (PI1-5) were then combined into a
weighted average to get an overall performance-index (PItotal), as shown in equation (2).
52
According to their importance and influence on overall performance, they were assigned
different weights:
Pilot scale as the first process step was considered to be the most important. In this step,
early foundations of future processes are determined and basic knowledge is gathered.
The more efforts at this stage are target-focused, the less effort is needed in later stages.
Thus, it was weighed w1=1.0.
The second and third process steps, full scale and technology transfer, are still important
especially regarding scale-up of the previously developed process. They both were
assigned a weight of w2=0.6 and w3=0.6.
The second to last step, launch, is considered to be less critical as it is fully based on
preceding efforts. It was thus weighed w4=0.2. This also applies to manufacturing
process efficiency, which resulted in a same weight w5=0.2.
(2)
)+(
+
)+(
+
(3)
53
0.76
Company J
0.75
Company Q
0.73
Company R
0.68
Company L
0.67
Company E
0.66
Company K
0.65
Company T
0.64
Company U
0.60
Company A
0.57
Company E
0.56
Company J
0.49
Company B
0.47
Company J
0.47
Company N
0.43
Company I
0.40
Company F
0.39
Company Q
0.30
Company Y
0.26
Company G
0.25
Company C
0.00
Company D
0.00
Company H
0.00
Company H
0.00
Company M
0.00
Company O
0.00
Company P
0.00
Company S
0.00
Company O
0.00
Company K
0.00
Company V
0.00
Company W
0.00
Company X
0.00
Company Z
0.00
Company AA
0.00
Company AB
0.00
Company AC
0.00
54
The overall performance (P) is a value between 0 and 1, with higher numbers indicating
a better overall performance.
From all 37 participants, only 20 had provided enough data to reliably calculate
performance (listed in Table 7
Participants with an overall performance of higher than 0.66 are considered to be high
performers. This leads to a high performer quota of 25%. Companies with multiple
participants are not grouped, but treated individually. Interestingly, the 5 high performers
were formed by 4 companies.
The overall performance (P) gives an indication how successful technical development,
especially process development, is.
)+(
+
(4)
55
Table 8 shows high performers and their corresponding values of integration. The values
are all between high (0.8) and very high (1). Thus it can be concluded that high
perceived integration is closely associated with high process development performance.
Table 8: High performing participants with the corresponding value of integration (n=5)
P
Company J
0.76
1.00
Company J
0.75
0.85
Company Q
0.73
0.80
Company R
0.68
0.97
Company L
0.67
0.93
Integration
1
0.75*
56
Integration (I)
0.90
0.80
y = 0.7652x + 0.4137
R = 0.566
0.70
0.60
0.50
0.40
0.30
0.00
0.20
0.40
0.60
Performance (P)
0.80
1.00
57
38.3%
100%
75%
30.2%
Rest
50%
Production
Development
31.5%
25%
0%
68.4%
72.0%
75%
71.0%
100%
other expenditures
50%
28.0%
31.6%
25%
29.0%
R&D expenditures
2009
2010
2011
0%
Figure 24: Average R&D expenditures in 209, 2010, and 2011 (n=15 for 2009, n=18 for 2010,
n=14 for 2011)
2009
2010
83.5%
64.2%
Generics/OTC 16.5%
35.8%
other expenditures
Innovators
82.0%
70.2%
Generics/OTC 18.1%
Innovators
0%
29.8%
Generics/OTC 17.7%
25%
32.5%
50%
Innovators
82.3%
75%
67.5%
100%
R&D expenditures
2011
Figure 25: Average R&D expenditures in 2009, 2010, and 2011 comparison of innovators
(branded drugs & biotech) vs. generics/OTC (n=10 for innovators in 2009, n=13 for innovators
in 2010, n=9 for innovators in 2011, n=3 for generics/OTC in 2009, n=4 for generics/OTC in
2010, n=2 for generics/OTC in 2011)
58
When comparing all participants, the average development costs between USD 300 Mio
and USD 900 Mio, the major part (36%) of all participants even indicated development
costs of under USD 300 Mio. Development of a product takes around 8-10 years or
slightly less (Figure 26). However, taking into account that research and development
efforts are much greater for innovators, the costs increase substantially: For R&D
intensive companies the average development costs are between USD 900 Mio and USD
1,200 Mio or higher (Figure 27). Unexpectedly, the development time does not differ
significantly (Figure 27). Most likely this is due to the fact that most development
projects have to move through the clinical development phases which take a similar
amount whether there were prior massive timely investments or not. Additionally, it is
believed that most participants rather considered development duration and neglected the
preceding research efforts.
a)
>1,200
Mio
14%
900-1,200
Mio
29%
<300 Mio
36%
b)
300-599
Mio
14%
<5 years
11%
5-7 years
26%
>12 years
0%
600-899
Mio
7%
11-12 years
21%
8-10 years
42%
Figure 26: Average development costs (a) and times (b) (n=29 for (a), n=27 for (b))
a)
>1,200
Mio
17%
900-1,200
Mio
33%
<300 Mio
25%
300-599
Mio
17%
600-899
Mio
8%
b)
<5 years
6%
>12 years
0%
11-12 years
19%
5-7 years
31%
8-10 years
44%
Figure 27: Average development costs (a) and times (b) of innovators (branded drugs &
biotech) (n=24 for (a), n=22 for (b))
In total, the average duration of technical development is 81.3 months. This is most
likely influenced by clinical development. The numbers below the process steps indicate
the average duration in months (Figure 28). However, since individual process steps can
run in parallel, this total number is not an absolute duration but rather representing the
59
resource effort. Almost half of all participants (45%) reach (clinical) POC during pilot
scale development and consequently clinical phase III follows directly and starts during
full scale development (Figure 28). This allows that products from that phase can be
used to supply the clinical study and do not go to waste. Over 60% of all companies
decide about the first manufacturing site right before full scale development starts and
can thus already consider the equipment of commercial scale production and coordinate
the set-up (Figure 28). The arrows indicate that the respective event occurs at other
process steps in some countries.
Figure 28: Duration of single process steps and indication of occurrence of selected milestones
(n=13 for process step duration, n=21 for occurences)
60
development helps to develop large scale processes that are already partly adjusted to the
equipment and set-up of the first manufacturing site.
Pilot Scale
18%
Full Scale
21%
35%
44%
negative
79%
rather negative
neutral
Technology Transfer 3%9% 12%
76%
rather positive
positive
Launch 4% 14%
0%
20%
29%
40%
54%
60%
80%
100%
Figure 29: Rating of the effect of integrated development on the performance of different
development stages (n=33)
Of all participants, 58% rate their development to be rather fully integrated and 18%
state it to be fully integrated (Figure 30). Thus, most participants consider their
development to be rather fully integrated. This concurs with the fact that most
participants work in cross-functional teams (Figure 31). ). This indicator is even higher,
which means that development projects are indeed mostly carried out in cross-functional
teams. However, personal ratings usually exceed the actual state. Although this value is
high, there is a lot of improvement potential with regards to existing concepts of
integrated development in the pharmaceutical industry.
20%
58%
40%
60%
18%
80%
100%
not integrated
rather not integrated
partially integrated
rather fully integrated
fully integrated
3%10%
0%
20%
61
27%
57%
40%
60%
80%
100%
strongly disagree
rather disagree
medium agreement
rather agree
strongly agree
62
Production
9%
Development
91%
no such group
15%
own organizational
unit
6%
Development
50%
Production
29%
Surprisingly, only little more than one-third (39%) of all participating companies do
possess designated launch sites (Figure 35). On average, there are 2.8 launch sites per
company, with a maximum number of ten different launch sites for one of the
participating companies (Figure 36).
63
No Launch Sites
61%
Launch Sites
39%
12
10
8
6
4
2.75
2
0
Launch Sites
Over 60% of all participants have designated teams for the launch of new products in
place, while only a small number of companies do not (Figure 37). Over 50% of these
launch teams are not directly reporting to routine Production at the first manufacturing or
launch site (Figure 38). This means that launch teams are rather site-independent, maybe
associated with or located at specific sites, but not reporting to it. It is also possible that
they are identical with the transfer group and are thus, as seen in Figure 33,
organizationally part of and also reporting to Development.
20%
29%
40%
60%
32%
80%
100%
not at all
rather not
somehow
rather
completely
64
Direct Reporting to
Routine/Commercial Production
20%
0%
33%
20%
40%
80%
100%
not at all
rather not
somehow
rather
completely
Figure 38: Extent of direct reporting to routine/commercial Production by launch teams (n=33)
In general, transfer from one development step to the following and associated with
this often also transfer from one specific cross-functional team composition to another
is considered to be problem-free (Figure 39). The more groups are involved, the less
smooth a transfer at interfaces will be, and the more problems will occur. On average,
smoothness of transfer at interfaces is the lowest before and during technology transfer.
This is mainly due to the fact that different organizations have to collaborate closely.
Employees in these different organizations, especially Development and Production,
have different ways of thinking and approaching problems (more freely and creatively in
development vs. more structured and process-oriented in production). This cultural
difference, often combined with varying expectations, makes transfers at these interfaces
most difficult. Especially in the end, in the time after validation up to launch, transfer is
mainly within Production and therefore smooth.
47%
47%
50%
44%
71%
29%
30%
60%
many problems
some problems
13%
Validation 5%
Registration
Registration Launch
Launch Post-Launch Improvements/
Changes & Maintenance
40%
14%
no problems, smooth
55%
27%
0%
39%
48%
73%
29%
20%
57%
40%
60%
80%
100%
Figure 39: Smoothness of transfer at interfaces during the development process (n=21)
65
100%
I
55%
45%
C
C
I
100%
I
C
La
un
c
gi
str
at
io
n
Re
h
Po
stCh Lau
an nch
ge
s & Imp
M rov
ai em
nt
en ent
an s /
ce
fe
r
43%
28%
28%
C
al
id
at
io
n
Tr
an
s
I
62%
C
38%
C
hn
ol
og
y
Te
c
Ea
rly
(la P ro
b
sc cess
Fi al e, De
na
v
f
l F eas elo
i
p
D orm bili me
ev u
t
el lat y) nt
op io
m n
Pi
en
lo
t
tS
ca
le
Fu
ll
Sc
al
e
process development.
38%
29%
52%
C
I
10%
C
60%
100%
C
11%
100%
C
C
C
Figure 40: Model of cross-functional collaboration (involvement and responsibility) during late
stage technical development
The percentages represent the amount of work done by the participant in the left column
during the process step in the top row. Cells with dashed boxes indicate responsibility
and leadership for the process step. Cells with I indicate that this participant is kept
informed during the process step; whereas C means that the participant is actively
consulted and thus slightly more involved.
Due to its non-technical nature, the process step Registration was not further
considered; it is mostly regulatory-driven and therefore not influenceable by the
company in a meaningful way.
It was obvious that in companies with the highest early manufacturing process
performance (P) the involvement of the main future customer the receiving/first
manufacturing or simply launch site started earlier during process development than in
lower performing companies (Figure 22, Figure 40). Also, the extent of cross-functional
collaboration was greater, meaning the different functions (mainly Development and
Production) are actually collaborating and finding solutions together.
66
As expected, the analysis showed that mass work load, and with it responsibility,
switched from Development to Production around the technology transfer step.
However, the true lead switched just after the technology transfer, after the process has
physically left development facilities and entered launch and commercial production
plants.
67
Team behavior
factors
Technical factors
70%
72%
80%
70%
63%
68%
80%
60%
37%
47%
20%
35%
70%
70%
20%
50%
53%
63%
40%
50%
Formal process
30%
49%
40%
55%
80%
73%
60%
65%
70%
69%
40%
60%
Team autonomy
40%
56%
40%
55%
Cross-team coordination
50%
57%
40%
45%
33%
50%
0%
40%
15%
41%
20%
30%
44%
60%
60%
65%
Knowledge of launch/first
manufacturing site capabilities and
equipment
73%
75%
80%
85%
Knowledge of secondary
manufacturing site capabilities and
equipment
52%
64%
25%
65%
High performers
average
High performers
Enabling factors
Industry average
Context factors
All participants
Table 10: Positive perception of success factors of all and of high performing participants
(n=30 for all participants, n=5 for high performers)
68
70%
80%
63%
All participants
80%
High performers
37%
20%
0%
20%
40%
60%
80%
100%
Figure 41: Positive perception of contextual success factors (n=30 for all participants, n=5 for
high performers)
70%
20%
53%
40%
All participants
30%
Formal Process
High performers
40%
80%
60%
0%
20%
40%
60%
80%
100%
Figure 42: Positive perception of enabling success factors (n=30 for all participants, n=5 for
high performers)
Encouragement to
Work Creatively
70%
40%
40%
40%
Team Autonomy
50%
Cross-Team Coordination
Formal Process for (Forward)
Knowledge Transfer
Formal Process for (Backward)
Knowledge Transfer
All participants
40%
High performers
33%
0%
15%
20%
0%
20%
40%
60%
80%
100%
Figure 43: Positive perception of team behavior success factors (n=30 for all participants, n=5
for high performers)
Development Equipment
Representing Equipment
at First Manufacturing Site
69
44%
60%
73%
80%
All participants
High performers
52%
25%
0%
20%
40%
60%
80%
100%
Figure 44: Positive perception of technical success factors (n=30 for all participants, n=5 for
high performers)
70
47%
Pilot Scale
20%
55%
Full Scale
20%
55%
Technology Transfer
Launch
All participants
20%
High performers
48%
0%
32%
25%
Routine Production
0%
20%
40%
60%
80%
100%
Figure 45: Knowledge management solution in different development stages (n=30 for all
participants, n=5 for high performers)
71
Minimum QbD elements are used throughout all development steps (Figure 46). It is
most often used during pilot scale development. However, even at routine production
over one-third of all participants use minimum QbD elements. As expected, this is more
spread than specific enhanced QbD elements such as DoE and PAT. DoE is used
extensively (over 60% of all participants) applied during pilot scale development, usage
then goes back especially during full scale development and technology transfer (Figure
47). PAT is even used fewer: around one third uses this enhanced QbD element during
early development steps, usage then decreases during launch and routine production
(Figure 48). This is somehow unexpected since PAT could ease launch and routine
production by eliminating delaying IPCs (in-process-control) and allowing real-time
releases. However, it would in turn require to be registered with regulatory authorities
exactly this way and could thus only be produced at sites with the PAT capabilities, i.e.
equipment and set-up. The following figures indicate how many of all and of top
performing participants only have mentioned the elements to be beneficial for success of
cross-functional collaboration.
53%
Pilot Scale
40%
45%
40%
Full Scale
52%
60%
Technology Transfer
All participants
High performers
41%
Launch
25%
33%
33%
Routine Production
0%
20%
40%
60%
80%
100%
Figure 46: Application of minimum QbD elements during selected development stages (n=30
for all participants, n=5 for high performers)
72
66%
60%
Pilot Scale
42%
Full Scale
20%
35%
Technology Transfer
Launch
Routine Production
All participants
20%
High performers
26%
0%
14%
0%
0%
20%
40%
60%
80%
100%
Figure 47: Application of DoE during selected development stages (n=30 for all participants,
n=5 for high performers)
35%
Pilot Scale
60%
34%
Full Scale
60%
33%
Technology Transfer
Launch
Routine Production
All participants
60%
High performers
26%
0%
21%
0%
0%
20%
40%
60%
80%
100%
Figure 48: Application of PAT during selected development stages (n=30 for all participants,
n=5 for high performers)
Very few companies deliberately refuse to use QbD elements such as minimum elements
or DoE (Figure 49). They are valuable during development to gain more knowledge in a
systematic way. PAT has the lowest value to development, its use is rather intended for
routine production to decrease losses and delays due to quality issues, and is thus refused
by more companies (30%). The most prominent reason to use either minimum or
enhanced QbD elements is to pursue a scientific approach (Figure 49). QbD elements
and especially DoE is used to generate knowledge and to gain process understanding. As
previously seen (Figure 47), this is mainly of interest during early development steps.
73
Over 50% use especially minimum QbD elements because of regulatory requirements
(Figure 49). More and more regulatory bodies do expected such minimum elements,
such as e.g. design space, to be included in registrations. Between one third and half of
all participants include minimum QbD elements or DoE in their registration documents,
PAT is only included by around one quarter (Figure 49). These numbers are rather low
but do reflect the companies desire to be flexible then it comes to transferring products
from high tech (e.g. with PAT-capable equipment) to low tech sites.
100%
79%
80%
68%
60%
50%
50%
44%
38%
40%
DoE
26%
20%
minimum QbD
18%
18%
21%
18%
26%
21%
15%
PAT
9%
3%
0% 0%
0%
Top
Meet
Scientific
Management Regulatory Approach
Decision Requirements
Regulatory
Relief /
Operational
Flexibility
others
Included in
Registration
Documents
Figure 49: Reasons for practicing minimum QbD, DoE, and PAT.
74
Too much loss of information and knowledge at interfaces: Transfer from one to
another group within cross-functional teams or changes of cross-functional team
compositions at hand-over points are the main source of information loss due to
unclear hand-over guidelines. In other cases guidelines might be suitable but are
not followed.
Cultural differences at interfaces: During changes of responsibility at interfaces
different cultures clash. Different groups have different ways of thinking,
working, and problem solving. This is mainly the case for inter-departmental
interfaces (e.g. Development and Production) and to a lesser extent also for
intra-departmental interfaces (e.g. formulation development and process
development).
Only few success factors proposed by literature appear to be important in the
context of pharmaceutical technical development.
Technical success factors are not found in the literature; however, they proved to
be very important in this study. Especially the knowledge about first
manufacturing sites capabilities and equipment seems crucial for successful
transfers.
Nonexistent knowledge exchange: Especially knowledge gained later during the
development process is not exchanged backward and thus might not be available
in future development projects. This way the same errors may occur repeatedly
and no general knowledge base is built up.
Nonexistent holistic knowledge management solutions: Often knowledge
management solutions are in place, but they are not based on a holistic system.
Each group or department has its own IT-based system and compatibility as well
as data-exchange are limited.
QbD application is still not established: Many companies more and more start to
implement QbD elements. However, these efforts are still small compared to the
potential benefits originating from a complete QbD supported science-based
approach to development and also routine production.
This chapter introduces two practical approaches to integrated development in the form
of two case studies. First, case study selection and concept are described. This is
followed by the actual two case studies. The chapter is concluded by a comparison of the
two case studies, a comparison with literature, and insights from case study research.
76
also other stakeholders present, e.g. members from Early Stage Development and
Transfer Organization. Additional to the workshops an internal survey was conducted at
each company. This was mainly to assess cross-functional collaboration during technical
development: which functions are involved to what extent during which development
step. The analyzed development process and contributing functions were more detailed
and company-specific than in the general industry survey. These company-specific
surveys were conducted internally to also analyze other functions perception of
technical development. The surveys at both companies had supplemental companyspecific questions about their current perceived situation in technical development and
about on-going improvement initiatives. They are not presented in detail; however, the
results are integrated in the cases.
Company: in this section the companys field of operation and markets, its plant
network, general organization, and products are described.
21
2.
77
3.
4.
Cross-functional collaboration: in this section the management of crossfunctional activities is described in more detail. Changing team compositions
and involvements along the development process are introduced.
5.
Potential for further improvement: this section discusses identified potential for
further improvement of the current approach.
The first case study has two additional sections: (1) improvement initiatives describes
on-going or past initiatives undertaken to improve the process itself and collaboration in
technical development and (2) QbD in practice.
78
Development activities are split in two: Early development activities are undertaken at
the companys research centers across Europe, the Americas, and Asia. Each of these
locations has specific areas of expertise and focus in their development portfolio, mainly
aligned with the research centers respective focus areas. Late development activities are
bundled and concentrated in the companys main development site near headquarter.
This split also reflects the collaboration needed for early and late development activities:
During early phases, mainly interaction with research is needed, whereas during late
phases, information exchange primarily happens with commercial Production.
Pharmaco1 has two designated launch sites used for introducing new products in either
the European or the American market. After successful launch, the launch sites produce
for the worldwide demand. Products can at a later stage be transferred to other, usually
technologically less sophisticated secondary manufacturing sites. Pharmaco1 is present
with manufacturing activities at 20 sites in 13 countries.
Technical development, including all development activities except clinical and medical
activities and spanning early and late stage development as well as technology transfer
and pre-launch activities, is, in comparison to other companies from the pharmaceutical
industry, further advanced than the average state-of-the-art. The systems currently in
place, namely their approach to seamless transfers, harmonization, and other
improvement initiatives, mark a desirable state for many companies. Internally, they are
perceived to be beneficial and are thus widely accepted among all involved employees.
However, in the sense of continuous improvement, the available approaches should be
kept up-to-date to reflect the ever changing circumstances.
With late development activities in focus, it can be said that the defined process is
working and established in practice. An internal survey has shown that all participants
rate Late Stage Developments performance to be high, 60% even very high. The fact
that over 50% of all participants noticed an increase in performance since implementing
the concept of seamless transfers is a good indicator for the effectiveness of recent and
current improvement efforts.
79
22
In most cases the change of manufacturing scale coincides with a change in equipment (size, location,
environment, manufacturer, etc.). Such changes always need intense testing, as process parameters might change
with even minor changes in equipment.
80
improvement and adaptation loop. If the final formulation and its process performance
are as intended, the project passes Drug Product Milestone 2 and moves from Early to
Late Stage Development.
During pilot scale development, the process is optimized to be ready for
commercialization. The adaptations to the process are rather minor and manufacturing
techniques are not changed, only if commercialization seems rather impossible23. First
in-process-control specifications and general process parameters are defined. Drug
Product Milestone 3 marks the start of development in commercial relevant scales.
During the scale-up of the manufacturing process from pilot scale to full scale, the
process is further optimized in order to meet conditions at commercial scale. Material
from full scale development is used as initial supply of clinical phase III. This phase is
used to gather more data on process parameters. Its primary goal is the development of a
robust and efficient manufacturing process, also considering QbD principles. When the
process is completely defined, running smoothly, and performance in a commercial
relevant scale is as intended, Drug Product Milestone 4 is reached and transfer to the
launch site is initiated.
During technology transfer, the product and the process as well as all accompanying
acquired knowledge are transferred from Development to the dedicated launch site.
Originally, it can be divided into two distinct phases: During evaluation (1) explorative
batches are produced to review and possibly adjust process parameters. This is mainly
due to the change in environment from Development to the launch site. Actual transfer
batches (2) are then produced exactly to the specifications. Acceptance of these marks
Drug Product Milestone 5 and concludes the technology transfer.
The following registration batches are used to generate data for the registration dossier as
well as to re-supply the still ongoing clinical phase III. Alternatively, previous
technology transfer batches can also be used24. Upon successful completion, the project
passes Drug Product Milestone 6.
23
This can have various causes: Usage of a new technology for which not enough commercialization knowledge
exists, early process development was made under time pressure and is not implementable in a larger scale, etc.
24
Initial supply of clinical phase III can be made with products from development. However, it is important that resupply is produced at the same site as the registration batches (usually the launch site). Otherwise it has to be
proven that the product from different environments is bioequivalent in the form of a bioequivalence study.
Development
Meetings
Joint
Manufacturing
Work
Contributions &
Interfaces
Development
Phases
Development
Milestones
Clinical
Development
Development
Responsibility
MS1
MS2
Hand-Over
Batches
Formulation Development
Phase I
Process Development
MS3
TechnologyTransfer
Launch Teams
MS4
Phase III
MS5
Registration /
Validation
MS6
Launch Teams
Phase II
82
Primary stability studies25 are then initiated. In parallel, the registration dossier is
prepared. Drug Product Milestone 7 is reached as soon as a concept for PAT application
as well as strategies to potential regulatory questions is defined.
When all relevant data is collected and the registration dossier is complete, it is finally
submitted to the regulatory authorities for registration. Upon successful acceptance,
launch batches are produced for product launch, followed by established commercial
manufacturing and initiation of clinical phase IV. Drug Product Milestone 8 marks the
review of the robustness of the commercial manufacturing process and possibly needed
improvements.
In general, all products are transferred from Development to one of the two launch sites.
There is no standardized process for the decision on additional or replacing secondary
manufacturing sites. Strategically important products usually remain at a launch site, but
are also transferred to a secondary manufacturing site in order to ensure contingency and
back-up capacity. Reasons for transferring products away from a launch site to
secondary manufacturing sites may include, but are not limited to: capacity at launch site
needed for another, more important product; high volume, low tech; low-cost
manufacturing; etc. Rather accurate market forecasts as well as clinical data must be
available for such decisions to be taken, usually after Drug Product Milestone 8.
Pharmaco1s development process is currently undergoing a transition from the
described process towards a process supporting the new validation guideline (FDA,
2011). Generally, the process in its entirety does not change; however, some phases will
be less rigid. The whole system will be more flexible and have an underlying continuous
flow towards registration. As implementation is still in progress and will not have
finished in the near future, it is not covered here.
25
Primary stability studies assess the long-term stability of the final packaged drug product.
83
The most important development unit at Pharmaco1 is the Core Team Development. It is
built up in a matrix structure and involves stakeholders from all major departments. The
team is led by the International Head of Development and consists of the following Core
Team Members: Medicine, Regulatory Affairs, R&D, Operations, and Marketing. All
core team members contribute to a different amount according to the development
progress. In the beginning, the team is influenced the most by the Core Team Member
R&D. As soon as clinical development starts, the Core Team Member Medicine takes
over. All others are rather supporting, e.g. providing clinical trial supply, publishing
clinical studies and their results, etc. The Core Team Member Operations is part of the
core team; however, Productions interest in the project in the very beginning is rather
small due to the high attrition rate at that stage. The core team is responsible for
advancing the development project through the Drug Product Milestones and reports to
the International Development Committee. This steering committee is finally responsible
for all decisions taken. Each R&D Project Leader directs around one to three
development projects. In core team meetings input from the various sub-teams is
presented by the respective core team member. On a quarterly basis, the R&D Project
Leader presents project results as well as team recommendations for decisions that need
to be taken to the steering committee, who are then taking these decisions. If milestones
are reached, the steering committee decides about milestone approval and senior
management initiates the next project phase.
All core team members lead an individual sub-team and take their sub-teams inputs into
the core team.
All team members of the Sub-Team Operations are from the Production department. The
core Team Member Operations is involved from the beginning and always part of any
decisions (especially regarding manufacturing technologies). However, their contribution
is limited in the beginning and is only increased when launch is approaching. Project
leaders of the Sub-Team Operations usually lead ten and more projects, so their attention
to single projects is very limited. This sub-team covers mainly quality topics, supply
chain management, logistics, purchasing and is mainly concerned about design to cost
as well as launch preparedness and launch readiness (e.g. how to best plan launch in
order to penetrate the markets in a most efficient way. The Sub-Team Operations is
formed around Drug Product Milestone 5.
84
The Sub-Team R&D is organized as a matrix structure and involves representatives from
both Development and Production. It is divided into a CMC and Bio Sub-Team, of which
only the first one is covered further. Among others, the CMC Sub-Team consists of
employees from Chemical Development and Production, Pharmaceutical Development,
process engineers (equivalent to Pharmaceutical Development but inside Production),
Analytical and Medical Sciences, QA and QC from both Development and Production,
and Packaging Development.
The team member
Pharmaceutics) changes over the course of the project: during early development the
Team Member Pharmaceutics is represented by a member of Early Stage Development,
in later development phases it is substituted by a member of Late Stage Development.
Early Stage Development is divided into different groups due to their different locations.
During early development activities, team leaders function as Team Member
Pharmaceutics in the superordinate Sub-Team R&D. Early Stages responsibilities
include trial formulations development, dosage finding, early formulation and process
development, definition of early in-process-control specifications, and final formulation
development.
Late Stage or Process Development consists of three project teams and one supporting
and enabling team. In the project teams the processes are developed. The team leaders
are representing the project in the superordinate Sub-Team R&D. They pass on the
current project status, next steps, and everything else discussed in the project team. The
supporting and enabling team mainly provides services such as risk assessments,
documentation, and other supporting functions to the project teams. There is a significant
amount of job rotation in Late Stage Development. The main reason is to educate
employees in other areas so that they better understand requirements and demands from
either Early Stage Development or Launch Teams. Besides this valuable learning, it may
also provide additional capacity when needed. In case of larger capacity shortages,
external employees can be acquired in order to still be able to deliver results. Late
Stages main tasks include: development of robust and efficient manufacturing
processes; consideration of QbD aspects; consulting during formulation development,
especially regarding manufacturing technologies, to facilitate commercialization;
responsibility of technology and know-how transfer from Development to launch sites;
support of activities up to registration and submission; manufacturing of material usable
85
for clinical trials; preparation of contributions to documents for clinical studies and
submission.
Process developments counterpart in the Sub-Team R&D is a Process Engineering
Team at the launch sites. This team is responsible for the development project after
successful technology transfer, forms the Launch Team, and is the direct partner of Late
Stage Development. Although this is an often used interface, they are differently
organized: Productions engineering team has substantially more employees than
Developments process development team.
Process Development is part of Developed and located at Pharmaco1s main (late stage)
development center. Transfer from Development to Production occurs from Late Stage
Development to a special Launch Team; however, there is no intermediate organization.
The Launch Team is part of Production and reports to the launch site. Pharmaco1 has
two designated launch sites with high technological standards.
86
member changes through the process, there is no single person responsible from end-toend, mainly to ensure that the project leader also holds specific expertise during all
development steps. R&D Project Management leads the project rather administratively
and mainly towards the upper steering committee.
All interfaces and hand-overs are well documented. The process is formal yet flexible
and tailored to Pharmaco1s situation and requirements.
For the internal survey about the collaboration along the development process it was
simplified into the most important steps (Figure 51).
Early Stage
Development
Pilot Scale
Full Scale
Technology
Transfer
PPQ* /
Validation
Registration
Launch
Post-Approval
Improvements
In total, 30 employees from Late Stage (9) and Early Stage Development (8), Production
(8), and R&D Project Management (5) participated in the internal survey. This provides
a representative assessment. The results show Pharmaco1s very intense and seamless
100%
C
I
C
9%
91%
C
C
I
52%
48%
C
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Q ss P
ua
lif erfo
ic
a t rm a
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La
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at
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Tr
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I
100%
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C
Te
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Fu
ll
Sc
a
Ea
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D Sta
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41%
59%
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12%
88%
C
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100%
C
100%
I
When a project enters technical development, the Early Stage Development group takes
over the lead. The Team Member Pharmaceutics is represented by an Early Stage
Development project leader at one of the Early Stage Development sites. Before Drug
87
Product Milestone 1, Early Stage confronts Late Stage with project plans and intentions.
Although this is only a paper assessment (no technical details are considered), it ensures
that development goes into a direction that is suitable for larger scales as well. Late
Stage is further informed from Drug Product Milestone 1 meeting on. During technical
development of the Intended Final Formulation, the Early Stage Development group is
doing all the work in lab scale by themselves. After around 60% of the work is done, a
member of the Process Development group (Late Stage Development) inspects the
process and its performance in lab scale at Early Stage facilities and defines further
measures to be taken before transfer to Late Stage as well as the upcoming transition
phase. Concluding early stage development, the transition phase begins: a hand-over
batch is produced by Early Stage at Late Stage facilities in pilot scale in order to analyze
product and process performance. Unsatisfactory analytical or performance data may
result in an additional re-work loop for Early Stage.
The project lead, represented by the Team Member Pharmaceutics, then switches from
Early to Late Stage Development. The currently available information and timelines are
discussed with both major involved functions Early Stage and Launch Group. Early and
Late Stage commonly perform a risk analysis which is derived into a development plan.
From then on Early Stage is only informed about the project. The development plan is
shared with the Launch Group so that they can prepare for potential technologies used
during later commercial manufacturing. During rather informal information meetings all
involved functions are regularly informed about the project. The Launch Group is
actively involved during full scale development. Representatives of the Launch Group
observe final full scale batches. The focus is on PAT technologies, mainly because these
technologies are taken over by commercial manufacturing. Often they measure data with
their own equipment in order to gain process knowledge applicable to commercial
manufacturing. With the successful conclusion of full scale development technology
transfer starts. Work is equally distributed between Late Stage and the Launch Group
and done in full collaboration.
If the conjointly produced transfer batches are accepted by the Launch Group,
responsibility (except for the drug registration) is handed over to Production. Late Stage
is supporting further activities from a consulting role and is on-site as trouble shooter.
Today, knowledge transfer along the development process is assured by (1) meetings
(milestone meetings, team meetings, preview meetings, etc.), (2) joint studies (e.g.
88
89
26
IPC stands for In-Process-Control and means the measurements undertaken in running processes in order to
measure quality during rather than after manufacturing processes.
90
Enhanced Implementation of
PAT Applications
26%
74%
75%
dis-advantageous
87%
beneficial
77%
74%
0%
20%
neutral
40%
60%
80%
100%
Figure 53: Internal perception of on-going and recent improvement initiatives at Pharmaco2.
91
approach should be adapted so that it meets not only Late Stage Developments
but also at least Early Stage Developments and Productions requirements and
constitutes a real benefit to these groups as well.
Improving the knowledge exchange culture between Early and Late Stage
Development as well as Production. This also includes trainings in other groups
activities and tasks (e.g. members of Early Stage Development should be trained
in late stage development activities in order to better understand requirements of
Late Stage Development and Production).
Implementation of an advanced knowledge management system. This can be
accomplished by either harmonizing existing systems (e.g. IT tools) or by
implementing a new system in order to facilitate knowledge exchange and data
access (one single, central place for storage with appropriate access rights). Such
a system is a valuable help in acquiring and reusing gained process and scale-up
knowledge.
Extended harmonization of equipment and processes between Development
and Production will further optimize and shorten the transfer process. However,
it has to be considered that the benefits must always be higher than the needed
efforts, thus excessive harmonization cannot be the ultimate goal.
92
In 2009 an initiative was started with the objective to define a new roadmap for
manufacturing evaluation, transfer, and registration batches. The concept titled
Optimization of Transfer from Late Stage Development to Launch Site had the
intention to optimize transfer processes in order to enhance common product and process
understanding as well as the implementation of joint manufacturing teams.
In 2011, this transfer concept was further developed by means of a concept paper
revision, including QbD aspects in the revised roadmap. QbD as a systematic approach
to development that begins with predefined objectives and emphasizes product and
process understanding and process control, based on sound science and quality risk
management (ICH, 2009, p.16) not only enhances pharmaceutical quality but also
increases process understanding and thus helps to develop robust processes.
This was reached with an early and consistent implementation of PAT to optimize scaleup and transfer. An additional benefit was to minimize the number of evaluation and
transfer batches, the batch size, and the transfer time. The focus of PAT application is to
understand and control the manufacturing process. A process is robust when all critical
sources of variability are identified, understood, and managed by the process and product
quality attributes. Pharmaco1 applies PAT early in process development in order to
acquire process knowledge and thus improve processes. It is also used to support IPC,
however, it does not substitute it and it is not planned to file PAT parameters with
regulatory authorities, unless required. PAT is used during technology transfer to get the
final data for registration. Overall, PAT application is widely distributed for internal use.
Concluding, PAT is mainly used for scale-up and transfer of processes: adjustments are
easier when process parameters can be monitored.
Pharmaco1s desired state of an early and consequent implementation of PAT to
optimize scale-up is not fully reached yet. One reason for not filing PAT with regulatory
agencies is that as of today the technologies and know-how are only available in
Development and at launch sites. Secondary manufacturing sites are not equipped
appropriately. As a consequence, filing of post approval changes including conventional
IPC methodologies would be mandatory.
There are potential advantages of implementing QbD in development. Mainly process
understanding is increased and thus scale-up is smoother. Full QbD will not be included
in registration because not all regulatory authorities accept it and thus completely
93
different concepts would have to be registered for different markets. Applying QbD or
related concepts (such as e.g. PAT) early in development improve scale-up and
technology transfer and also have a great impact on operational excellence in
commercial manufacturing.
In an internal survey at Pharmaco1 different obvious benefits in implementing QbD
elements were identified (Figure 54). Early and extended application of enhanced QbD
elements, such as PAT, will add to an increased process understanding and help build up
a valuable knowledge base to simplify future development projects. Consistent
application will further optimize scale-up and technology transfer (the impact of
implementing enhanced QbD elements is to get a beneficial process understanding).
Operational Flexibility 7%
Reduction of
7%
Post-Approval Changes
24%
69%
dis-advantageous
33%
60%
neutral
beneficial
Process Understanding 0%
0%
100%
20%
40%
60%
80%
100%
Gaining process knowledge and monitoring and control of manufacturing processes are
the most beneficial aspects of PAT (Figure 55). Additionally, efficiency increase during
process development and transfer is perceived to be a further benefit of PAT
implementation.
94
86%
93%
dis-advantageous
neutral
18%
0%
75%
25%
20%
40%
beneficial
57%
60%
80%
100%
95
Pharmaco2 covers a focused range of research areas. There are six research centers in
Europe, the Americas, and Asia. Each of these centers focuses on specific therapeutic
areas as well as market access to specific regions. Pharmaco2 actively collaborates with
various research institutes and other pharmaceutical and biotechnology companies across
the globe.
All research centers are involved in early development activities related to their focused
therapeutic area. However, there are two distinct Science Centers, located in Europe
and the USA respectively, coordinating all development activities undertaken at the
different research centers. This set-up allows vast interaction mainly in the transition
phase between late research and early development activities while simultaneously
following a centralized approach. Late development activities are mostly done by the
Science Centers, where late stage development capabilities are concentrated and
connections to commercial Production are most efficient.
In Pharmaco2 there are several pilot plants, each representing a scaled-down commercial
production environment. This allows adapting to commercial requirements in a rather
sub-commercial scale during an early phase of development and optimizing processes
for the transfer to commercial manufacturing. However, these plants are often not
available due to limited capacities. In such cases, either external or commercial capacity
has to be acquired. The use of pilot plants implicates a rather early decision about the
future manufacturing site.
A substantial number of development projects are outsourced at Pharmaco2. As a
general rule, development is done internally if capacities are available, (technological)
capabilities already exist, or costs of building-up technology capabilities and knowledge
are beneficial. In general, external development needs much less internal resources and
does not influence the critically observed headcount. Often the outsourced development
projects are not internalized but rather manufactured by a third-party-manufacturer as
well.
Pharmaco2 has a network of production sites in 11 countries. Transfer of commercial
products between different manufacturing sites occur and follow a similar concept as
technology transfer from development to first manufacturing sites.
There exist powerful and above-average concepts for pharmaceutical development and
technology transfer towards more cross-functional collaboration and less silo-thinking
96
and -acting. The main challenge for Pharmaco2 is to thoroughly implement and live
these concepts as well as to continuously adapt them to the ever changing circumstances.
27
IP stands for intellectual property and basically means the patent protection by law.
97
Based on this and additional data, at Gate 1 it is decided whether to proceed to drug
discovery or to abort the project. The activities leading to the following two Milestones
deal with further research, pre-formulation, and regulatory strategy. Gate 2 marks the
decision to proceed to Early Stage Development. At that time, detailed strategies for
regulatory, CMC, and clinical are defined and a global development plan specifying
early dosage form, time-to-market, costs, etc. is created. Gate 2 triggers official project
initiation, where a concept including timings, costs, and risks and a development plan
(project plan) are created. Project execution then follows after approval by the highest
board. The project and its major outcome, a clinical candidate, are transferred to
Development, which is now responsible.
This marks the start of Tech Transfer Pre-Phase. Formulation development starts by
screening different formulations in order to identify the best one. In parallel, the
manufacturing process associated with the chosen formulation is developed. During that
phase, there is a tremendous overlap between formulation and process development. It is
also used to develop analytical methods (e.g. for stability tests). First considerations
regarding primary and secondary packaging are made. Generally, all processes are in lab
scale, meaning a few hundred grams up to one or two kilos. More extensive process
development (e.g. kind of granulation, kind of coating, etc.) starts with a one kilo scale
and includes screening technologies, general process investigation, and identifying
process parameters. During Tech Transfer Pre-Phase non-clinical safety studies (the
results mark Milestone 5), clinical phase I (the results mark Milestone 6), and clinical
phase IIa are conducted.
Right before the end of clinical phase IIa and when the process is ready to be upscaled, the development project moves to Tech Transfer Phase 1. The goal of this phase
is to develop and scale-up capable processes, meaning they are robust and controllable
within specified ranges. Therefore Pharmaco2 uses a scientific approach: in (scale-up)
experiments it is assessed what parameters vary, then the reasons are identified, and in
the end strategies for controlling these variations are developed and applied. At the end
of clinical phase IIa POC is reached. This marks Milestone 7 and means that the
manufacturing strategy as well as estimated manufacturing costs are determined. The
manufacturing strategy also contains the decision on the first commercial manufacturing
plant. Information about the (potential) receiving (first manufacturing) plant is gathered
in order to consider these specific settings and equipment. Reaching POC also means
98
that the project moves from Early Stage to Late Stage Development. When the final
formulation development is finished, the manufacturing process scale-up starts: in pilot
plants the process is scaled-up from a few hundred grams to 5-20 kilos. The environment
in pilot plants is very close to the one in the first manufacturing plant. The process is
continuously adapted to meet the specifications. Material from pilot plants (pilot scale)
can be used to supply on-going clinical studies. If the quality is right, it can later even be
used as initial supply for clinical phase III. In the case of internal development and
extensive technology knowledge, controllable risks, and capabilities at the first
manufacturing plant, the pilot scale can be omitted and scale-up is done from few kilos
to few hundred kilos. Further scale-up to commercial scale occurs at the first
manufacturing plant. During scale-up, primary and secondary packaging development is
finalized and stability data is collected. Clinical phase IIb runs in parallel to process
scale-up. At Gate 3, based on clinical phase II results, it is decided whether to proceed
with development and start clinical phase III.
Tech Transfer Phase 2 marks the actual transfer from pilot or intermediate to full or
commercial scale and along with this from Development to the first manufacturing plant.
It starts when it has been shown that scale-up is possible and process development is
completed. Tech Transfer Phase 2 is usually executed prior to or during clinical phase III
to assure that (re-)supply is in a relevant scale and can be used for validation and
submission. Material from commercial scale production is used to (re-)supply clinical
phase III (initial supply can be from pilot scale production). Tech Transfer Phase 2
covers the development of analytical procedures, scale-up to commercial relevant scale,
further process adaptations, and stability testing. Full scale batches show that the process
works (can be used for clinical re-supply). While clinical phase III is running, a detailed
commercial and pre-launch plan is established at Gate 4. Milestone 8 marks the end of
clinical phase III, where results are analyzed. At the end of this phase the project
responsibility is transferred to the Transfer Organization.
99
100
During Tech Transfer Post-Phase, the transferred process is validated and the
submission documents are generated. Eventually, the project is filed for submission at
Gate 5. After a successful launch phase, the product is transferred to business at Gate 6.
The project then enters post-approval continuous verification and improvement: the
process and especially the critical process parameters are monitored and controlled so
that the specifications are constantly met. Upcoming manufacturing issues are usually
handled by the manufacturing site; however, in case of analytical or regulatory issues
Developments Maintenance Team is involved.
Pharmaco2 does not yet follow a complete QbD approach. So far, a scientific approach
and singular QbD elements are used and it is planned to adopt more of QbDs general
ideas. Reasons for this are mainly to obtain more robust processes, to gain more in-depth
process knowledge, to meet regulatory requirements, and to get easier approval with a
QbD aligned development process. However, Pharmaco2 has yet not finally concluded
whether a full blown QbD approach is really paying off.
101
technology transfer and thus from Development to Production. It has members from Late
Stage Development and from the Transfer Organization as well as from the final
receiving site.
The Transfer Organization is the major bridge between Development and commercial
Production. The organization is part of central Production, which also holds other
functions like global supply chain, global purchasing, etc. Central Production is without
any manufacturing site, it is mere a service organization within Production.
There exist several pilot plants for specific product families. They are all used during
internal development according to their capabilities. Thus they fully belong to
Development.
Another functional unit is called Maintenance. It is part of Development; however, it is
not involved in primary development activities. Its main tasks are related to commercial
manufacturing with focus on analytical and regulatory issues (compared to processrelated problems handled by the manufacturing site).
Process development is part of Pharmaceutical Development (R&D) and to a large
extent concentrated at Pharmaco2s two science centers. Transfer from Development to
Production occurs from Late Stage Development via an intermediate organization to a
commercial manufacturing team. The intermediate or Transfer Organization is part of
central Production, but does not report to a specific manufacturing site. Its main task is
the coordination between Development and commercial Production. It is the
Development counterpart in Production and closely collaborates with commercial
Production. Pharmaco2 has no designated launch sites the first manufacturing site is
chosen for each project specifically, based on capacity and capabilities.
102
is mainly due to Pharmaco2s rather small size and thus limited resources as well as
intense collaboration with CROs28 and CMOs29.
For the internal survey about collaboration along the development process, Pharmaco2s
development process was consolidated into seven simple but representative process steps
(Figure 57).
Early Formulation
Development
Early Analytical
Development
Early Packaging
Development
Early Process
Development
(Lab Scale)
Final Formulation
Development
LateStageDev.
Technology
Transfer
Document
Technology
Transfer
Technology Transfer
Late Process
Development
(Lab / Pilot Scale)
Final Analytical
Development /
Analytical
Validation
Final Packaging
Development
Process
Validation
Report of
Equivalence
Product Launch
Post-Launch
Improvements
LateStageDev.
Process
Validation
Report of
Equivalence
Product
Launch
Post-Launch
Improvements
28
CRO stands for contract research organization. Basically this denotes a company offering research and
development services.
29
CMO stands for contract manufacturing organization. Such a CMO or third party manufacturer offers
manufacturing as service.
103
Transfer Phase 1 start is when the Transfer Organization is joining the project team. This
is also around the transfer from Early to Late Stage and when clinical POC is reached. In
the beginning, the collaboration is limited to extended information sharing from
Development to Production (e.g. receiving meeting minutes). The collaboration then
intensifies the more late stage development advances. At the beginning of scale-up,
information about the receiving plant is being collected (e.g. exact equipment, setting,
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capabilities, etc.).
Pharm. Development
Transfer Organization
Production
QA
Regulatory
Marketing
100%
I
I
I
I
78%
12%
10%
C
I
54%
29%
17%
C
I
22%
30%
48%
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28%
27%
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I
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31%
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19%
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104
105
106
107
improve transfers. Knowledge management was mentioned in the literature, but not with
the importance it was found to be mentioned by both companies.
QbDs
growing
popularity.
However,
todays
knowledge
This chapter introduces a descriptive model for integrated development. Insights from
the case studies and the industry survey refine the reference framework and transform it
into a descriptive model.
The first sub-chapter provides an overview of the benefits of integrated development
concepts. The second chapter presents the descriptive model built upon the reference
framework and findings from the empirical investigation as well as case study research.
Finally, in the third sub-chapter general conclusions are drawn.
110
2.
3.
111
improvements and optimizations are not needed during the first years of
commercial manufacturing.
4.
Implementation of such a concept comprises side-effects that are valuable for the
development of organizational properties:
1.
2.
3.
4.
112
The model is extended to also incorporate the important topic of knowledge management
and is now comprised of four main components (Figure 60): (1) The actual management
of the development process within integrated development approaches, (2) the
characteristics of the organizational set-up of involved organizations and departments,
(3) supporting and enabling success factors, and (4) knowledge management. Also, to
reflect a true management perspective, the component cross-functional collaboration in
the research framework is transformed into managing cross-functional collaboration
and deals with management aspects rather than with actual team composition.
113
commercial production. Moreover, the more commercial the scale is, the more they
should also be available to transfer group or even production engineers.
Launch sites are typically multi-purpose sites and are thus very flexible regarding
manufacturing capabilities. This is beneficial for product launches and can be used to
quickly start-up commercial production. Still, to maintain this flexibility, products
should be transferred to secondary manufacturing sites. In the case of a low degree of
alignment of manufacturing capabilities, this transfer can be very expensive. Therefore it
is important to have some level of harmonization across all manufacturing sites.
Development teams are organized as matrix-teams and thus truly cross-functional. It is
important that technical responsibility is always with the function or department leading
all work related activities. However, it is favorable for the overall project success that
responsibility during development projects does not change. This also prevents
knowledge loss and effort at responsibility hand-overs.
114
site, are kept informed. This way they can start to prepare their increasing involvement at
later stages.
When a project enters scale-up, meaning the transition from lab to pilot scale, first
considerations about the future manufacturing site must be made. Thus, the Transfer
Organization, in possession of the manufacturing sites capabilities and equipment, must
be involved when the first manufacturing site is determined and the manufacturing
strategy is developed. Traditionally, development engineers are influenced by research
and are therefore rather open to innovation and new technologies. Manufacturing
engineers on the other hand, know their existing and proven technologies and, for
economic reasons, rather want to use what already exists and what is understood.
Therefore it is important that both engineering groups discuss whether Developments
ideas can be operationalized on existing equipment and capabilities or whether new
technologies have to be built up. When manufacturing engineers are involved in
selecting new technologies and also see the advantages, they are more open to adopting
them. Moreover, the earlier technologies are built up, the more effective they can be used
in commercial production.
During full scale development it is important that the chosen first manufacturing site is
involved and contributes to the success of the project. This can be achieved by providing
either development capacity (e.g. commercial equipment) in a commercial scale
environment or knowledge about commercial scale behavior and properties. In the end it
is important that the outcome is a full scale manufacturing process that is adapted to
commercial productions capabilities and equipment. During this phase commercial
production gets ready for the following technology transfer: composing a manufacturing
engineering team, assigning capacities for technology transfer, adapting long-term
planning for commercial production after launch, etc.
Technology transfer is still under Development responsibility; however, it is functionally
led by the Transfer Organization. This organization is also coordinating the technology
transfer. Both Development and Production are collaboratively executing technology
transfer and conjointly manufacturing first evaluation batches at the first manufacturing
site. As this is the phase with the most exchange and where two different approaches
meet, it is most important that collaboration is fostered and the functionally leading
Transfer Organization coordinates and connects both functions. Developments goal
must be to transfer a nearly optimal full scale process with only minor needs of
115
adaptations, in order to successfully launch the product in the end. On the other hand,
Production also wants to take over adapted processes and thus sees the need of
collaboration also during earlier phases (e.g. pilot scale, as mentioned).
The following validation is under Production responsibility. It coordinates all efforts
between Development and Production. During validation a mixed team of Development
and Production validates the process at commercial manufacturing. This also helps to
build up further process knowledge.
Technically, Production is responsible for registration. However, the relevant work is
carried out by regulatory. Both Development and Production provide the data necessary
for successful registration. Technical aspects of the launch are done by commercial
production.
Post-launch improvements and changes are handled by engineers from commercial
Production. However, the Transfer Organization is coordinating the acquired knowledge.
It is passed on to Development and thus ensures company-wide learning. Moreover,
Development can directly benefit from such inputs as they can be applied in future projects.
It is important that all major hand-overs, i.e. from Early to Late Stage Development and
from Late Stage Development to the Transfer Organization or commercial production,
are considered carefully. Rather than one group finishing work and handing it over
abruptly, the goal is to collaborate around and across the interface. The closer a handover comes, the more the succeeding group is involved and exchange increases. Ideally,
some hand-over batches are produced conjointly. After the actual hand-over, the giving
group assists the receiving group by consulting. This involvement then decreases as the
receiving group acquires more knowledge. By applying this process adaptation the
interfaces will blur and the transfer will be seamless and smooth.
Other functions and departments are constantly informed and updated as the
development project progresses and masters milestones. They are involved when needed
and according to their expertise. For example: After the definition of the final
formulation, primary and secondary packaging development starts. Marketing is then
involved as they have all the market insights and knowledge about how to design
packages in order to reach optimal customer acceptance. Moreover, these other functions
often support processes secondary to technical development and are therefore not
explained in detail.
116
117
118
119
6.3 Conclusion
In a successful approach to integrated development in the pharmaceutical industry,
development projects follow a formal process with clear roles and responsibilities.
Process development is under responsibility of Late Stage Development. Ideally, a
Transfer Organization exists, belonging to the Production department and thus really
representing productions capabilities. The Transfer Organization is involved in process
development and represents the commercial manufacturing or launch site. Thereby it is
assured that the environment, equipment, and capabilities of commercial production are
considered and processes are specifically developed to be efficient in commercial
production. The Transfer Organization takes over responsibility from Development after
successful technology transfer. As soon as commercial production is established,
responsibility is transferred from the Transfer Organization to routine production. The
Transfer Organization becomes active again in case the production is transferred to a
secondary site at a later stage.
Top management commitment and an organizational climate fostering cross-functional
collaboration are important for successful concepts. Thereby all needed resources are
available and employees are encouraged to collaborate with other departments.
Furthermore, common goals and visions are important for development project success,
to eliminate silo-thinking and to foster individual interest in overall project success. This
overall team and project performance can also be rewarded. The more equipment and
capabilities of development and commercial production are aligned, the smoother the
transfer runs. Harmonization efforts further increase process stabilization.
120
Not yet widely established but crucial are singular, integrated knowledge management
solutions. They help to build up and preserve valuable knowledge, which can then be reused for new development projects, speeding up development time and decreasing
efforts. However, it is important that there is only one system in place, and that data is
available to all responsible employees at all time. This knowledge can then also be used
to resolve manufacturing issues. A scientific approach to development is based on an
accessible, large amount of data and empowers preventive process stabilization.
Generally, it is highly beneficial to establish a culture and common understanding of
continuous improvement philosophy throughout the company. This means all employees
on all levels act towards the goal of increasing effectiveness and efficiency of all
processes. To achieve such a general mindset of continuous improvement, it must be
demonstrated by leaders. Furthermore, employees must be trained in order for all to
share the same understanding and to see the benefits. If it is routine to regularly question
the current way, what has changed, and what could be improved, a true culture of
continuous improvement is established.
according
to
empirical
findings.
The
model
contributes
to
the
122
Research finding 1b: The earlier production is integrated into the development process,
the higher the process development performance is.
This finding is tightly connected to the first finding and extends it further. The high
performing companies all showed very early integration: a gradual increase of
production involvement and final complete hand-over after technology transfer.
Improvements after launch were also found to be very integrated, meaning Development
was again involved and could thus also learn for future projects.
Earlier involvement of production requires excellent coordination. A Transfer
Organization can exhibit this function and operate as a bridge connecting Development
and Production. It can be an organization on its own or this role can be taken over by
launch sites. From the importance of this function, research finding 2 is derived:
Research finding 2: To bridge Development and Production, a Transfer Organization is
needed.
Existing known success factors critical to integrated and cross-functional development
are tested and in some cases found to be highly relevant for the pharmaceutical industry
as well. However, others do not apply to this specific industry, or at least their effect is
not as expected from examples of other industries. From this, research finding 3a is
formed:
Research finding 3a: The four organizational success factors top management
commitment, organizational culture fostering cross-functional collaboration, common
goals and visions, and clear roles and responsibilities are most influential.
Contrary to expectation, team co-location and formal knowledge transfer process proved
to be negligible for high process development performance in the pharmaceutical
industry.
Additionally, an additional group of success factors, i.e. technical success factors, is
introduced and their importance demonstrated. Especially equipment harmonization is a
perspective not considered in literature so far and thus generally extends theory. It forms
research finding 3b:
Research finding 3b: Harmonization and knowledge about capabilities are crucial
technical success factors.
123
124
between
development
facilities
and
first
commercial
manufacturing plants. If this is not possible due to too many sites or limited
resources, at least detailed information about capabilities, capacities, equipment,
and technologies of each commercial manufacturing plant should be collected
and taken into account early during development.
Knowledge Management: Knowledge management proved to be increasingly
important. Todays more scientific approach to development generates immense
amounts of data. It is only efficient to collect them all if they are made accessible
for other projects. Therefore management should implement a single, integrated,
and holistic knowledge management solution. Such an effective system increases
the value of knowledge by making it highly re-usable and therefore generating
potential to eliminate previously performed experiments.
125
QbD: Crucial for QbD implementation is the generation of data that can be reused for future development projects. A growing scientific data base unfolds
QbDs potential as its initially high efforts (mainly for data generation) decrease
significantly. Whether management should aim for QbD-submissions cannot be
answered and is probably a question of a companys philosophy. However, even
if QbD is used for internal purposes only, it greatly increases process
understanding and fosters the scientific approach to development.
126
Furthermore, data representing the current situation regarding cross-functional cooperation was gathered by internal surveys. Therefore a RACI-matrix-style questionnaire
listing all process steps as well as participating functions was widely distributed to
representatives from Development, Production, and other functions within Pharmaco1
and Pharmaco2. Participants provided information to what degree or amount they are
involved in certain process steps along drug product development. A clear advantage of
this method is that all involved functions get a chance to describe the situation from their
point of view. However, the main disadvantage is that there is no agreement in the end.
There is not one single collaboration and involvement process for the participating firm,
but rather multiple different versions, all to some extent biased by the participants.
However, significant discrepancies in single process steps can be taken as problem
indicator. Usually, after discussion, it turns out that some participants have either used a
different definition of that particular process step, some participants have not filled out
the way it is in reality but rather in theory (which indicates that either theory or
execution has to be reviewed), or that some participants do not know the theory and have
not yet adapted to it. The result is either adaptation of the theory or education and
training of the desired state. It also has to be taken into account that all results are mere
perceptions of the individual participants.
The pharmaceutical industry can be divided into the generics, biologics, and
traditional pharmaceutical industry. They all share a very similar development
process, but there are also some minor differences. Investigations of all three
sub-industries could reveal differences or similarities in the way cross-functional
collaboration is organized. Furthermore, it could be that each sub-industry has
unique combinations of success factors driving efficiency.
2.
127
QbD is still not very widespread in the industry. A holistic investigation of how
to implement it, what resources are needed, and what the real benefits are would
certainly help, in case it is favorable for QbD implementation, to increase its
popularity. There exist studies in some of these fields; however, to date it has not
been researched in a holistic approach.
4.
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Curriculum Vitae
Name:
Date of birth:
Place of birth:
Basel, Switzerland
Education
2008 2013
2007 2008
2004 2007
1993 2002
Professional Experience
2008 2013
2007 2008
2001 - 2006
2002 2004