Single Use Technology A Practical Guide to Design and Implementation 2nd Edition Adriana G. Lopes

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Adriana G. Lopes, Andrew Brown
Single-Use Technology

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Author
Dr. Adriana G. Lopes
Biopharm Services
Unit 1 (1st floor)
Chess Business Park
Moor Road
Chesham HP5 1SD
United Kingdom
Adriana.g.lopes@gmail.com
Dr. Andrew Brown
Allergan Biologics Ltd
Estuary Commerce Park
Estuary Banks
Speke
Liverpool L24 8RB
United Kingdom
ucbeaib@gmail.com
ISBN 978-3-11-064055-7
e-ISBN (PDF) 978-3-11-064058-8
e-ISBN (EPUB) 978-3-11-064067-0
Library of Congress Control Number: 2019934969
Bibliographic information published by the Deutsche Nationalbibliothek
The Deutsche Nationalbibliothek lists this publication in the Deutsche
Nationalbibliografie; detailed bibliographic data are available on the Internet
at http://dnb.dnb.de.
© 2019 Walter de Gruyter GmbH, Berlin/Boston
Cover image: Science Photo Library / LOOK AT SCIENCES / EURELIOS / PATRICE
LATRON
www.degruyter.com

Preface
As the biopharmaceutical industry matures, trends towards
increased flexibility and productivity, faster time to market and
greater profitability are driving the replacement of traditional
stainless-steel equipment by single-use technology (SUT). SUT
use in the biopharmaceutical industry can impact the efficiency
of manufacturing processes by reducing capital costs,
improving plant turn-around-times, reducing start-up times
and costs, eliminating non-value added process steps, and
reducing the risk of cross-contamination. SUT has the potential
to significantly reduce liquid waste, labour costs and on-site
quality and validation requirements. SUT such as bags for
preparation and storage of buffers have been used for many
years to support bioprocessing activities. However, in recent
years, SUT have been developed that can be applied to the
majority of processing operations that can be found within the
biopharmaceutical industry. For some of these operations,
application of SUT is new and immature, which can present
new challenges and risks to the end-user. In addition, there
remain many unknowns regarding the way these technologies
should be implemented into a validated, commercial GMP
environment. This handbook aims to describe the activities that
must be undertaken by the end-user to select and design
technologies to meet requirements and implement SUT.
Chapter 1 starts by providing an introduction to SUT
advantages, risks and the overall implementation process. Chap
ter 2 outlines recommended guidelines from regulatory

agencies for adoption of a systematic science- and risk-based
approach throughout the lifecycle of the development of
medicinal drugs. Application of these approaches in the context
of SUT implementation is discussed. This chapter also provides
an overview of implementation plans, with emphasis on team
structure and the use of risk-mitigation approaches. Chapter 3
describes considerations during SUT selection based upon a
technical feasibility study and the business case of the system,
as well as selection of a SUT supplier. Chapter 4 considers the
specification and design of SUT systems. Chapter 5 underlines
steps to validate a process using SUT. Chapter 6 presents case
studies of key concepts applied to SUT technologies, such as:
bag systems; bioreactors; tangential-flow filtration;
formulation; and fill-finish. Here, considerations during the
selection of off-the-shelf systems and custom-designed SUT
assemblies are presented, whereby technical and business
comparisons are made. Selection of appropriate material for a
certain application and preliminary tests that must be
undertaken are outlined. Examples of specification and design
for each SUT system used for each application are presented,
alongside process descriptions and flow diagrams. Risk
assessments applicable to the design, processing and quality of
the active pharmaceutical ingredient (API) are shown. Based on
these assessments, qualification of the final SUT assemblies is
presented. This handbook is the first comprehensive
publication that describes the practical considerations that
should be adopted at each stage of SUT implementation within
biopharmaceutical facilities.

Contents
Preface
1 Introduction
1.1 Benefits and limitations of single-use technology
1.1.1 Improved process flexibility
1.1.2 Increased speed of implementation
1.1.3 Cost savings
1.1.4 Increased product safety
1.1.5 Technical limitations
1.1.6 Cost increases
1.1.7 Increased complexity
1.1.8 Dependence on suppliers
References
2 Strategies for implementation of single-use technology: A
risk- and science-based approach
2.1 A risk- and science-based approach
2.2 Implementation plan
2.3 Risk-assessment tools to support implementation
References
3 Feasibility assessment of single-use technology and suppl
iers
3.1 Technical feasibility
3.2 Business assessment
3.3 Selection of a supplier of single-use technology

References
4 Specifications and design of single-use technology
4.1 Framework for the design project
4.2 Design choices and risk
4.3 Specification
4.4 Design verification
References
5 Validation
5.1 Qualification of materials and assemblies
5.1.1 Integrity
5.1.2 Compatibiliy
5.1.3 Sterility and cleanliness
5.2 Process qualification
5.2.1 Installation qualification and operational qualification –
W
ater or buffer runs
5.2.2 Process simulation –
Media fills
5.2.3 Performance qualification –
API stream
5.3 Continuous improvement of processes
References
6 Case studies
6.1 Case study 1: Single-use bag systems
6.1.1 Material selection
6.1.2 Risk assessment for extractables and leachables
6.1.3 Profiles of extractables and leachables
6.1.4 Specification and design
6.1.5 Qualification of final bag assembly
6.2 Case study 2: Single-use bioreactor
6.2.1 Selection of single-use bioreactor technology
6.2.2 Specification and design of single-use bioreactors

6.2.3 Risk assessment of the single-use bioreactor process
6.2.4 Qualification of single-use bioreactors
6.3 Case study 3: Tangential-flow filtration
6.3.1 Selection of technology for tangential-flow filtration
6.3.2 Specification and design
6.3.3 Risk assessment to support design of a system
6.4 Case study 4: Formulation and fill-finish
6.4.1 Selection of fill-finish technology
6.4.2 Risk assessment of fill-finish
6.4.3 Qualification of fill-finish operations
References
Abbreviations
Appendix 1 Scoring Tables
Appendix 2 Risk Rating and Priority Number
Index

1 Introduction
Recent trends in the biopharmaceutical industry derived from
technological advances (e.g., increased drug potency and
smaller niche markets targeting patient-specific drugs) have
resulted in the need for flexible manufacturing facilities.
Further achievements in engineering cell lines capable of high
production titres has led to a decrease in the volumetric
manufacturing capacity needed to align with market
requirements. Concurrently, the previous decade has seen the
development of single-use technologies (SUT) applicable to
biopharmaceutical manufacturing from the simplest and
widely used bag systems and filters to more complex systems
such as bioreactors, chromatography and fill-finish operations.
As a result, industrial adoption of SUT has increased gradually,
and end-users are considering application of the technology to
operations discounted previously due to technical or scale
limitations. Increased adoption of SUT has also brought about
the realisation that new challenges are encountered to select,
specify, implement and maintain the technology throughout the
lifecycle of the active pharmaceutical ingredient (API). This
handbook has been written to provide practical guidance on: (i)
considerations for the end-user to review while choosing
technologies to apply to processes; and (ii) implementation of
SUT.
The route by which a process for the manufacture of
biological products is designed, implemented and qualified can
be long and complex. It requires the input of multi-disciplinary

teams and there are many risks of failure. For example, the
process can fail if it cannot be controlled to provide reliable
batch-to-batch consistency of the product with sufficient
quality. Exposure to risks by a particular organisations is
dependent upon its experience with the product, process,
manufacturing technologies and scale of operation. Many
single-use systems are considered to be ‘mature’ because they
have been present on the market for >10 years, been through
design changes to improve performance, and have been utilised
across a wide range of scales and manufacturing scenarios,
from clinical through to commercial. However, other SUT are
‘immature’ and require more time to implement due to limited
knowledge, availability and adaptability of the technology.
There are no standardised approaches for SUT implementation.
Instead, the implementation strategy should be ‘tailored’ based
upon the type of technology and level of expertise of the end-
user.
Compared with traditional stainless-steel systems, additional
risks must be considered when using SUT. A comprehensive list
of these risks is shown in Table 1.1. They have been grouped
based upon impact to the end-user, supply chain, material and
process.
These risks illustrate the range of capabilities that end-users
must possess within their organisation, or that they will need to
leverage from the supplier or third-part service providers to
implement SUT. Hence, some end-users continue to employ
traditional stainless-steel systems that they have expertise with,
or adopt a ‘hybrid’ approach whereby implementation of SUT is
used to support process operations that use stainless-steel tanks
(e.g., media/buffer preparation, hold, addition or waste
collection). However, irrespective of whether the SUT is
adopted fully or partially, the end-user should develop a robust

implementation strategy so that risks are detected and
mitigated in a timely manner.
Table 1.1: Risks involved in adoption and use of SUT.
There are many similarities between a project to implement
a SUT and the traditional design approach for a stainless-steel
system. However, there are differences, particularly in relation
to the timing of when decisions are made and the criteria that
are assessed. An overview of the key phases for implementation
of SUT is laid out in Figure 1.1. An implementation plan should
be developed at the start of the project and updated as progress
is made, and a better understanding of the technology is
developed. The end-user should start with assessment of the
feasibility to use the SUT system for a given application, which
should include technical and business assessments of the
technology. Selection of an available supplier of SUT should be
evaluated concurrently. Depending upon the complexity of the
SUT for a given application, or maturity of the system, trial of a

given system may be necessary before the technical feasibility
can be completed. This strategy requires the co-operation of the
SUT supplier, but should start with the end-user specifying the
requirements of the system, including how it integrates with
the wider process and facilities. At the end of the feasibility
assessment, a decision to proceed with a preferred supplier is
made. Hence, investigation of the quality and robustness of the
supply chain of the supplier should be considered as part of this
selection process. Once selected, the implementation plan
should be updated when better understanding of regulatory
acceptance of the SUT, system reliability and, above all, the
resulting impact upon the quality of the product is known. A
process-control strategy is required to ensure measurement of
product quality, process interaction and validation. This
strategy should underline the level of acceptable risk to the API
in terms of cross-contamination, adsorption, and
extractables/leachables from the SUT material that is product
contacting, as well as process risks in terms of system integrity,
process adjustments and operator safety. Specification, design
and validation should ensure that the SUT system is fit for
purpose so that, once implemented, it continues to support
continued manufacture of the API to the required quality level.
Once validated and in use, performance of the SUT should be
monitored with metrics fed back to the supplier to ensure that
issues are identified and dealt with in a timely manner.

Figure 1.1: Key focus areas during SUT implementation.
1.1 Benefits and limitations of single-use
technology
As the biopharmaceutical industry matures, the trends are
towards the higher flexibility and responsiveness of production
facilities as well as reduction of manufacturing costs and
timelines in a background of increasingly strict regulatory and
capacity demands. SUT can support an end-user to benefit from
these trends but limitations do exist with the technology.
1.1.1 Improved process flexibility
By decoupling the process train from the facility infrastructure
and transforming the facility into separate individual
workstations it becomes easier to reconfigure the facility to
meet changes in product scale or the type and number of
products to be manufactured. The end result is greater
flexibility with regard to the process and product. The
portability of the equipment means that manufacturing spaces
can be re-purposed as required. In addition, capacity can be
increased through scale-up or scale-out, with minimal or zero

impact to support systems such as water-for-injection (WFI) or
generation of clean steam. As a result, SUT enables the drug
manufacturer to increase manufacturing capacity and/or
respond rapidly to market demands. If product demand
increases, rapid expansion of capacity can be achieved by
adding together similar SUT units with no need for
implementation of process changes or improvements [1].
Single-use systems provide easier handling and quick
turnaround times between batches and manufacturing
campaigns due to the removal of clean-in-place (CIP),
sterilisation and re-qualification activities [2]. This strategy
improves process flexibility, and is particularly useful for multi-
product facilities where assurance is required that the
equipment is cleaned appropriately between batches of
different products.
1.1.2 Increased speed of implementation
Faster construction, commissioning and launch of facilities can
be achieved by using SUT. This is driven by the reduction in
complexity of secondary support systems that would otherwise
lead to longer design, fabrication and qualification activities.
Single-use systems save time and money due to rapid product
change-over and associated validation studies with minimal
risk to product integrity, and results in accelerated time to
market [3]. It also means that capital decisions can be delayed
without impacting timelines for drug development. This
approach reduces the risk that a decision to build a facility is
taken when the capacity required is unclear or likely to change.
If a manufacturer of a drug for clinical trials requires to build a
clinical facility, SUT is much faster to implement than a
traditional stainless-steel facility. Also, the overall costs of

implementation are lower so, if the drug fails clinical trials, it
carries a reduced risk to the business due to the flexibility of re-
configuration to a new product and reduced capital costs.
1.1.3 Cost savings
sually, single-use systems are supplied pre-sterilised (by gamma
radiation), thereby eliminating the need for CIP or steam-in-
place (SIP) support systems, areas and procedures, as well as
the equipment maintenance associated with these practices [4].
Reduction of capital investment costs for process equipment is
achieved by elimination of utility requirements for CIP and SIP
capabilities, and reduction of the number and size of CIP skids
[2, 5]. Due to elimination or reduction of CIP and SIP
requirements, generation of purified water (PW) can also be
reduced in scale and cost for new-build facilities.
SUT also results in better utilisation of facility assets. The
reduced scale of SUT equipment (smaller facility footprint)
results in reduced fixed costs (e.g. investment, operation,
maintenance) and a ‘better utilised facility’ that can respond to
higher demands in production by process intensification.
1.1.4 Increased product safety
Single-use operations result in a reduced risk of cross-
contamination and increased assurance of sterility [6] due to
elimination of cleaning between batches and the associated
validation. The low detection limit assays used to measure
contaminants after cleaning, combined with the lack of
acceptable cross-contamination levels, increase the risk
associated with cleaning procedures. SUT systems are used only
once for a specific process and operate in a closed-system

environment, which prevents cross- contamination of product
and protects operators. A closed system also allows different
operations to be undertaken concurrently in the same room
while minimising the impact on heating ventilation and air
conditioning (HVAC) airflows and pressure differentials.
1.1.5 Technical limitations
The main limitations of SUT are based on the scale of operation
as well as the ease of scalability and operability. Available
bioreactors using disposable technology may reach only ≤4,300
l (working volume, 3,500 l), and disposable chromatography
columns have diameters of ≤60 cm. Scale limitations are
typically due to the strength and durability of the plastic
material. In general, SUT are not recommended if they are
likely to come into contact with organic solutions, or in
operations requiring high heat removal transfer or high mixing
rates.
Some SUT provide scalable options but the end-user would
have to use the same system and supplier. Scaling up or down
between different technologies is more difficult due to the lack
of inter-changeability between them as well as different system
designs and configurations. Sometimes, unconventional and
unproven scale-up/down methodologies must be considered [7].
Finally, the process performance of a SUT system may not have
been proven completely compared with the traditional
stainless-steel equipment it is intended to replace. Main
concerns involve the ability to deliver similar mixing, pressure
and flow rate, as well as control capability to deliver a process
and product reproducibly and consistently.
1.1.6 Cost increases

Use of SUT leads to increased operational costs resulting from
repeated use of consumables or items that would otherwise be
manufactured from stainless steel. If items are used once per
batch then there are also increased costs derived from waste
disposal, which need to be managed internally. Depending upon
the number required, cost and availability of single-use items,
these may become the drivers of cost of goods. Facilities with
high use of SUT have an added emphasis on logistics and
workflows resulting from the changed requirements of storage
and manual transport of process liquids, equipment,
consumables and waste, as well as redesigned personnel flows
[8, 9].
1.1.7 Increased complexity
Lack of maturity of some SUT systems (and associated
operational experience) poses new challenges and risks. Ease of
use may not be proven fully within a manufacturing
environment, or the robustness of the system may not be
known from clinical to commercial scales. The number of SUT
systems available for a particular application may be limited.
Lack of standardisation across suppliers in the utilisation of
materials and connections as well as integration with hardware
also increases the amount of design and review work required,
and reduces the ability of the end-user to identify secondary
source suppliers. As a result, there are limited options for inter-
changeability and connectivity between similar technologies.
There is a lack of guidelines and standard procedures for the
use and validation of SUT. Use of SUT introduces new
requirements for validation of plastic product contact
materials, such as integrity, sterility, and compatibility with the
product. An example of this absence is the test conditions used

for assessment of extractables, where standard methodology is
lacking [10].
Complexity can also arise from the tubing arrangements,
assembly and disassembly of single-use components, operation
of sterile connections between equipment and components, and
steps required to achieve a leak-free environment. Design
approaches can be taken to reduce this complexity, particularly
if a SUT is implemented across an entire process. However, a
new layout of the facility, work flows and training approaches
are required so that operational handling errors are minimised.
1.1.8 Dependence on suppliers
A major concern for SUT use is the dependence on suppliers to
provide a consistent and cost-effective supply of systems that
meet the required quality specifications [11]. SUT require
repetitive purchases, and suppliers must be certain that they
have sufficient capacity to ensure a consistent supply of single-
use components. In turn, the end-user must have detailed
understanding of the supply chain of the SUT and must
consider inventory management and storage capability.
As mentioned above, the limited availability of
components/parts and restricted interconnectivity between
different technology/suppliers places considerable emphasis on
selection of the appropriate supplier and materials provided.
Selection of suppliers and qualification of the vendor’s quality
systems becomes very important to ensure robustness of the
supply chain.
The potential advantages of SUT presented above can make
a compelling case for adoption. To minimise risk, the
disadvantages should form the basis of the considerations that

need to be evaluated during the selection and implementation
of this type of technology.
References
[1] C. Valle, Filtration Separations, 2009, 46, 18.
[2] A. Sinclair and M. Monge, Pharmaceutical Engineering, 2002, 22, 1.
[3] T. Kapp, BioProcess International, 2010, 8, S10.
[4] Pall Corporation, GDS Publishing Ltd., Bristol, UK, 2011. [Private
Communication].
[5] A. Sinclair and M. Monge, BioProcess International, 2011, 9, 12.
[6] J. Robinson and B. Bader in Proceedings of the Interphex Conference &
Exhibition 2008, Pennsylvania Convention Center, PA, USA, 2008, p.1.
[7] R. Eibl, S. Werner and D. Eibl, Advances in Biochemical
Engineering/Biotechnology, 2009, 115, 55.
[8] N. Guldager, Pharmaceutical Technology, 2009, 33, 68.
[9] M. Monge, BioPharm International, 2006, S43–S51.
[10] A.G. Lopes, Food and Bioproducts Processing, 2015, 93, 98.
[11] A. Ravise, E. Cameau, G. De Abreu and A. Pralong, Advances in
Biochemical Engineering/Biotechnology, 2009, 115, 185.

2 Strategies for implementation of
single-use technology: A risk- and
science-based approach
The amount of resources and effort required when
implementing single-use technologies (SUT) are dependent
upon the scope of application and risk factors identified in Tabl
e 1.1. If application is in a manufacturing environment, then
understanding the impact upon product quality is important.
Also, the ease of use and quality of single-use components must
be acceptable. If the application is late-stage clinical or
commercial manufacturing, then the robustness and reliability
of the supply chain will be important factors. If the end-user
has little experience in working with SUT, or is investigating use
of SUT for a new application, then effort will be required to
assess and test the SUT to ensure that it is suitable. If the SUT is
being considered for a single-unit operation, then
implementation will require less effort than if the SUT is being
applied throughout an entire process or facility.
An approach for SUT implementation is presented in Figure
2.1. The degree to which the approach is applied varies
depending upon the scope of application. There are three key
phases to implementation. First is the initial assessment of the
feasibility of the SUT to an application. The key milestone
reached at the end of this phase is identification of feasible
options to proceed and investigate further. The second phase is
the design and selection of the SUT from a supplier. The

milestone at the end of this stage is sanction of capital to
implement the SUT selected. During this phase the design is
finalised, and systems are procured, qualified and launched.
The goal of this phase is the release of a single-use system for
use within a manufacturing process.
Various aspects of the implementation approach will be
explored throughout this handbook and the relevant sections
are indicated within Figure 2.1. Key concepts of the approach
are:
1. An implementation plan is developed that addresses the
requirements of all stakeholders and considers (from the
beginning) the criteria required for successful
implementation;
2. A multidisciplinary team should be assembled with
knowledge of the process in addition to operations, quality,
engineering and logistics;
3. Design considerations should be considered early in the
implementation approach, and the preferred technology
should be tested at scale by operational personnel before
making purchasing decisions; and
4. A systematic science- and risk-based approach should be
adopted to identify and mitigate risks reviewed throughout
the implementation approach. Risk areas considered
should include technical, business, quality and supply
chain.

Figure 2.1: Recommended approach for SUT implementation. BOM:
Bill of materials; FAT: factory acceptance test; GMP: good
manufacturing practice(s); QA: quality assurance; QC: quality
control; R&D: research and development; SAT: site acceptance
testing; SWOT: strength, weakness, opportunities and threats
analysis; and URS: user requirements specification.
2.1 A risk- and science-based approach
The regulatory bodies that oversee development and
manufacture of therapeutic drugs have numerous published
guidelines that guide companies in their activities. Many of the
principles covered in these guidelines are applicable to the
selection and implementation of new technologies. Key aspects
are to build quality and undertake risk assessments throughout
the implementation process to ensure that the technology
works as intended and does not impact upon the active
pharmaceutical ingredient (API) quality. Current good
manufacturing practices (cGMP) guidelines for pharmaceuticals

set by the Food and Drug Administration (FDA) require the
industry ‘to integrate quality systems and risk management
approaches into its existing programs. . .’ and state that ‘
quality
should be built into the product’ from the development phase
and throughout the lifecycle of a product [1]. ‘The FDA has
identified a risk-based orientation as one of the driving principles
of cGMP initiative . . . The goal is to use a scientific framework to
find ways to mitigate risk while facilitating continuous
improvement and innovation in pharmaceutical manufacturing
in the context of risk- and science-based approach’ [2].
GMP guidance from the FDA states that industry should use
technologies that facilitate conformance with cGMP and
streamline product development [2]. In the case of SUT, they aid
conformance with GMP and can streamline operations through:
1. Reduced cleaning and potential for contamination;
2. Dedicated equipment and/or disposable parts;
3. Simpler change-over between products in multi-product
facilities; and
4. Use of closed process equipment to alleviate the need for
stricter classification of rooms.
To integrate quality systems and risk-management approaches,
the International Conference on Harmonisation (ICH) has
established quality standards and requirements. The relevant
guidelines are:
– ICH Q8 ‘Pharmaceutical Development’ [3] incorporates
elements of risk and quality by design;
– ICH Q9 ‘Quality Risk Management’ (QRM) [4] relates to
quality and GMP compliance; and
– ICH Q10 ‘Pharmaceutical Quality System’ [5] covers the
lifecycle management of process and system control.

The outcome of the risk-management framework is intended to
lead to a science-based decision undertaken across the lifecycle
of a product. In the case of a SUT, because it is not fully mature,
several sources of risk arise, particularly those derived from
material/human failure or a lack of knowledge of working with
such technology. These risks are presented in Table 1.1 and
should be addressed by an end-user as they seek to adopt SUT.
ICH Q8 presents the concept that quality should be built into
the drug product from the beginning (i.e., starting with the
design process) and is, therefore, not solely reliant upon
retrospective testing of product or intermediates. This strategy
relates to manufacturing systems in that a ‘quality by design’
approach is used to ensure that critical aspects are designed
into systems during the specification and design process, and
are documented alongside their acceptance criteria in a
suitable manner. Assurance that manufacturing systems are fit
for intended use [e.g., material attributes or control of critical
process parameters (CPP)] should be monitored and evaluated
continuously throughout the lifecycle of the system. API and
process information as it relates to drug product quality and
patient safety, should be used as the basis for making science-
and risk-based decisions. This approach is seen as a means to
ensure that manufacturing systems are designed and verified to
be fit for their intended use.
API and process information can come from many routes:
scientific investigation; previous manufacturing experience;
understanding of regulatory frameworks and their
applications. A company may already have considerable API
and process understanding to leverage depending upon the
maturity of the drug product. Regardless of the initial level of
experience, knowledge will increase as the end-user progresses
through the design, verification and implementation process.

This knowledge should be captured and communicated so that
it can be used effectively and decisions re-assessed.
API and process information that should be considered or
analysed further includes critical quality attributes (CQA) of the
API, CPP, and information on the process control strategy. The
definition of CQA and CPP as stated by ICH Q8 [3] are:
– CQA is a physical, chemical, biological or microbiological
property or characteristic that should be within an
appropriate limit, range, or distribution to ensure the
desired product quality; and
– CPP is a process parameter whose variability has an impact
on a CQA and, therefore, should be monitored or controlled
to ensure the process produces the desired quality.
The SUT may in its operations have a direct or indirect impact
upon CQA. Risk- assessment tools should be used to identify the
level of impact, and ensure that suitable steps are identified and
taken to mitigate the risk during design and implementation
phases. The design and implementation process can be
considered to be successful if the equipment and facilities with
the corresponding control systems achieve the requirements
for CPP or CQA and eliminate (or control appropriately) risk to
the patients. Verification activities after implementation should
define acceptance criteria based on these critical aspects and
should be documented. If manufacturing systems meet the
required criteria, then they show evidence that they are fit for
the intended use. A focus upon CQA of manufacturing systems
should lead to efficient use of resources, but verification
inspection and tests should not be limited to only critical
aspects.
In accordance with ICH Q9, risk management should
underpin the specification design and verification process with

the focus on risk to product quality and patient safety. ‘The
evaluation of the risk to quality should be based on scientific
knowledge and link to the protection of the patient. The level of
effort, formality and documentation of the quality risk
management process will depend upon the level of risk to product
quality and patient safety’ [4]. Quality risk management (QRM)
is a systematic process for the assessment, control,
communication and review of risks to the quality of the
(medicinal) drug product across the product lifecycle. It
supports a scientific and practical approach to decision-making.
QRM provides documented, transparent and reproducible
methods to accomplish steps of the QRM process based on
current knowledge about assessing the probability, severity and
(sometimes) delectability of the risk. Organising data and
facilitating decision-making through cause-and-effect diagrams
(also called Ishikawa or Fishbone diagrams) and failure mode
effects analysis (FMEA) provides an evaluation of potential
failure modes for processes and their likely effect on outcomes
and/or CPP and CQA. Higher risks should have a higher level of
control and documentation. Risk-management tools can also be
utilised to assess and control the robustness and performance
of the SUT and the quality of the supply chain.
The QRM process consists of a series of steps that begin with
initiation of the process, in which the scope is defined. A risk
assessment is conducted to identify hazards, and to analyse and
evaluate the risks associated with these hazards. Risk related to
the design and implementation of manufacturing systems
includes the impact of technological novelty or complexity in
addition to vendor/material risks upon product quality and
patient safety. If risks cannot be eliminated, then controls are
considered to reduce the risk to a level whereby they are
acceptable. The result of risk assessment is communicated out

to the wider organisation, and is reviewed on a periodic basis to
ascertain if events have impacted upon the evaluation and
acceptability of the risk.
Use of API and process information as well as QRM enables
implementation of ICH Q10 effectively and successfully across
all stages of the drug product lifecycle [5].
ICH Q10 facilitates innovation and continuous improvement
of process performance, API quality, the QRM system, and
strengthens the link between development and manufacturing
activities. The objective of the quality system is to maintain a
system that delivers product with appropriate quality attributes
consistently. This objective is achieved by using QRM to monitor
and control systems, process performance, and product quality.
In the case of SUT systems, the quality system extends to the
control and review of outsourced activities and quality of
purchased materials (including management of
responsibilities). Ultimately, the end-user company is
responsible for ensuring that processes are in place to assure
control of outsourced activities and the quality of purchased
materials.
Using a science- and risk-based approach for SUT
implementation is paramount for identification, quantification
and management of the critical sources of variability that may
affect API quality. Control strategies can be used to maintain a
state of control and facilitate continual improvement applied
throughout the product lifecycle.
2.2 Implementation plan
Outlining a project plan with detailed timescales,
responsibilities of individual stakeholders, and deliverables is

paramount to the success of the SUT implementation strategy.
The project manager (end-user) should hold implementation
meetings to determine levels of support available from each
stakeholder and to identify the critical activities to be
undertaken during the course of the project. Goals and
milestones should be defined, and teams and responsibilities
should be delegated as required to ensure timely delivery of
tasks. An implementation checklist is shown below:
– Describe goals and objectives.
– Identify the roles and responsibilities of stakeholders (Figure
2.2).
– Identify impacts/bottlenecks and methods to overcome or
mitigate.
– Identify resources that are needed and if they are available,
the desired completion date, and constraints.
– Subdivide the implementation plan into steps (Figure 2.1).
– Identify key milestones/decision points to be tracked.
– Project paths and methods of progression tracking.
– Schedule team meetings.
The implementation process is a team effort involving
stakeholders from procurement (supply chain), planning,
operations or manufacturing science and technology (MSAT),
process engineering, quality, and the SUT supplier. Subject
matter experts (SME) should take the lead role in verification
that, based upon their area of expertise and responsibility, the
manufacturing systems are appropriate. Responsibilities
include defining verification strategies, acceptance criteria,
selection and execution of appropriate test methods, and
review of results. A strong collaboration with the SUT supplier
is advisable, but may not be required if the organisation has
good experience with the SUT for the scale and purpose that it

is to be applied. Otherwise, the SUT supplier should be part of
the project team to provide expertise in SUT technology, along
with help with the integration into existing technologies,
operations and systems. Figure 2.2 lists the project team and a
summary of its tasks and responsibilities during SUT
implementation. The make-up of the team will probably change
throughout the project because not all SME are required from
the beginning of the project.

Figure 2.2: Members and responsibilities of the implementation
project team.

Implementation of SUT starts with factors that determine if
application of the SUT system for a given application is feasible.
Here, assessment of technology and the business case is drawn
(more details are given in Sections 3.1 and 3.2). Criteria for
selection and evaluation of a particular SUT are listed. If any of
the high-level criteria are not met then single-use systems for
the envisaged application may not be applicable. The risk-based
strategy starts when choosing which SUT to implement. After
initial definition of the process, a supplier is selected and SUT
components or assemblies identified. The importance of
ensuring compatibility of equipment and material is
paramount for ensuring the quality of the final drug product.
Equally important is to undertake initial assessment of the
manufacturing process, quality systems and sourcing of
materials when choosing the SUT supplier. A risk-based
approach should be applied when evaluating the security of
supply and qualification of SUT suppliers. Some of the risk-
mitigation strategies concern identification of alternative
vendors and alternative options for disposable parts. An
alternative and preferred SUT options can be tested
concurrently to reduce risk.
A risk-based approach should also be applied during the
design, qualification and continued verification steps. During
the design stage, the project team is responsible for undertaking
a risk assessment to identify CPP for SUT operations and
consider the impact on API characteristics before the validation
process. A risk assessment of all individual single-use
components, assemblies and support equipment is undertaken
at this stage to demonstrate no risk or a risk-mitigation strategy
to drug product quality and patient safety. Outcomes of the risk
assessment form the basis of a process validation approach that
ensures that manufacturing systems are fit for purpose when

implemented, and that they will continue to support continued
manufacture of the drug product.
Validation and qualification studies must demonstrate the
suitability of the SUT system for the end application. Examples
include:
– API compatibility
– Studies on microbial control and impurities
– Hold studies to establish acceptable product/intermediates
hold durations
– Growth and yield of cells (in the case of culture bags)
– System integrity
– Testing of leachables
Validation requirements are justified based upon risk-based
activities such as criticality and impact assessments. These
identify critical and non-critical systems and their components;
and then evaluate whether the systems have a direct impact on
the product quality, purity, safety and effectiveness.
Once the process and system is qualified, then continued
process verification is required. The aim of this activity is to
monitor and control performance, including process changes,
vendor change notifications and undertaking periodic re-
qualification and maintenance. Risk analysis is also useful
during this verification stage because it aids identification of
failure in operating parameters that fall out of a proven
acceptable range or, in a worst-case scenario, upon
process/system robustness. Risk analysis ensures that controls
are in place to alert users if process variables start to fall out of
control.

2.3 Risk-assessment tools to support
implementation
Risk assessment consists of identification of hazards followed
by the analysis and evaluation of risks associated with exposure
to those hazards. Risk is a function of two contributing factors:
probability of occurrence and severity of harm. The higher the
two factors, the higher is the overall risk.
Various risk-assessment tools are designed to support a
scientific approach to decision-making. Common examples
include checklists, flowcharts, process maps, cause-and-effect
analysis (Fishbone) diagrams, preliminary risk assessments
(PRA) and control charts. Other more formal tools referred to in
ICH Q9 are: FMEA; hazard analysis and critical control point
(HACCP); hazard and operability studies (HAZOP). These
methodologies should be selected according to their suitability
for a particular application. For example, the HACCP is more
suitable when the drug product has been launched because it
facilitates monitoring of critical points in the manufacturing
process. The HAZOP is usually undertaken during the design
stage to evaluate process safety hazards and deviations from
normal use (original design intent).
The overall process of risk management is described in ICH
Q9. It starts with identification of the risks and hazards
associated with each step of process. A PRA can be used at the
earliest stage in the design process to identify risks if
uncertainty remains and few parameters have been defined [6].
In effect, it is a ‘brainstorm’ of ‘what if’ scenarios and
alternative design options. The cause-and-effect analysis of each
individual hazard identified can be visualised in a Fishbone
diagram. The latter presents the product or process in the main

‘spine’, and the secondary ‘spines’ are different factors or
causes of hazards. The hazard can be derived from failures in
materials, controls, personnel, equipment and procedures.
Once the risk and source have been identified, assessment of
the impact of potential failures can be undertaken and
quantified. The impact or criticality of the risk can be assessed
by measuring its severity and probability of occurrence against
the number of controls required to eliminate or reduce risk to
an acceptable level. This analysis can be undertaken in a FMEA,
which is a tool used to: identify potential failures; examine their
impact upon product quality; propose adequate corrective and
preventive actions. The FMEA includes quantification of the
following aspects related to risk:
– Severity (S), or how significant the deviation is in terms of
product quality and patient safety;
– Occurrence (O), probability and frequency of occurrence;
and
– Detectability (D), which includes controls and methods to
detect deviations (or their associated parameters).
The severity, occurrence and detectability of risk are multiplied
to obtain a risk priority number (RPN) that is used to
differentiate which areas carry more risk. The higher the RPN,
the greater the need of additional controls and/or more
frequent re-qualification processes than others.
Based upon FMEA results, a control strategy for the
identified hazards should be implemented, monitored and
reviewed continuously. The FMEA can be used to assess risk at
different stages of SUT implementation. It can be undertaken
during design of a single-use final assembly or equipment to
assess the risk of failure of components or assembly method.
The FMEA can also focus on process failures (CPP) to ensure

reproducibility between batches or the product quality
(whereby the impact upon CQA is the main focus). The FMEA
can, therefore, aid determination of which critical processes
require design verification and process validation. Examples of
risk assessments applied to all stages of SUT implementation
and specific to different bioprocess operations (e.g., upstream,
downstream, fill-finish operations and process support systems)
are presented in Chapter 6.
References
[1] Quality Systems Approach to Pharmaceutical cGMP Regulations,
Department of Health and Human Services, Food and Drug
Administration, Rockville, MD, USA, September 2006.
[2] Pharmaceutical cGMPs for the 21st Century –
A Risk-based Approach,
Department of Health and Human Services, Food and Drug
Administration, Rockville, MD, USA, September 2004.
[3] International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use, Pharmaceutical
Development Q8(R2), ICH Harmonised Tripartite Guideline, Step 4 Version,
International Conference on Harmonisation, Geneva, Switzerland,
August 2009.
Registration of Pharmaceuticals for Human Use, Quality Risk Management
Q9, ICH Harmonised Tripartite Guideline, Step 4 Version, International
Conference on Harmonisation, Geneva, Switzerland, November 2005.
Registration of Pharmaceuticals for Human Use, Pharmaceutical Quality
System Q10, ICH Harmonised Tripartite Guideline, Step 4 Version,
International Conference on Harmonisation, Geneva, Switzerland, June
2008.
[6] J. Vesper in Risk Assessment and Risk Management in the Pharmaceutical
Industry, Parenteral Drug Association, Bethesda, MD, USA, 2006.

3 Feasibility assessment of single-
use technology and suppliers
Selection of single-use technologies (SUT) should first focus on
determination of whether application of a SUT for a given
application is feasible. This determination should include a
technical and business assessment of the technology in addition
to review of the available suppliers and their capabilities. The
first step of this evaluation is assessment of whether the
technology will meet process requirements such as operation,
product yields and quality. Limitations in terms of scale or
technical performance that could impact upon the required
outputs should be considered. The cost of investment and the
cost derived from operation of the system should consider
scale, infrastructure requirements (support systems and
utilities), regulatory requirements [biosafety, good
manufacturing practices (GMP), room grades] and the
experience and training of personnel. The logistical control
strategy impacts upon facility requirements in terms of storage
and material release. In addition, a strategy to guarantee
security of supply and qualified vendors is very important.
When choosing a SUT, the supplier will become a business
partner: this is a key decision and should be included as a part
of the system selection from the early stages. Some of the
considerations when choosing suppliers are: the service
support provided to clients; quality of SUT supplied; and track
record of continuous supply of SUT of appropriate quality.

3.1 Technical feasibility
Not all SUT are mature, and even those that have been utilised
for many years and across a wide range of applications may not
fit the specific application of end-use. In all instances where the
application is new to the end-user, thorough technical
evaluation should be carried out. The first step of this technical
feasibility analysis involves preliminary assessment of the types
of SUT available and the suitability of system to achieve the
intended aim. Table 3.1 summarises the technical criteria
related to process, operations, facility and the SUT that should
be considered during this stage.
The technical criteria during processing should address the
suitability of the plastic material under normal operating
conditions (volume, pH, temperature, pressure, flow rate) and
the resulting impact on process, product yield and quality. The
sterility of single-use components is important because the
method of sterilisation can affect material properties and
require additional validation.
Scale of operation and scalability of the system should be
assessed to ensure that the limits do not impact upon the end-
use. For example, single-use bioreactors (SUB) are available in
discrete sizes up to a scale of 4,300 l (working volume, 3,200 l).
Table 3.1: Technical criteria to be reviewed during assessment of the technical
feasibility of SUT.
Process (Figur
e 3.1)
– Materials of cons
truction and physical properties (biocompatibility and
leachables)
– Scale of operation/size
– Physical attributes and process parameters (time,
pressure, temperature, volume, pH, mixing, flow rates)

Another Random Document on
Scribd Without Any Related Topics

We remained in Landrecies until Saturday, August 29, expecting daily
to be returned to our own people in accordance with the terms of
the Geneva Convention. Our destination, however, was fated to be in
the opposite direction. Under an escort of half a dozen German
soldiers, commanded by an under-officer, we marched out of the
town, up the hill where the battle had taken place, to Bavay. It was
a tiring journey for the wounded men lying in ambulance wagons.
The Hon. R. Keppel was the only wounded officer. He traveled in a
wagon with certain men of his regiment, with whom he appeared to
be on exceedingly friendly terms. Two of the occupants of that
wagon had lost an arm each, and they were the cheeriest of our
party.
It was dark when we reached Bavay, and everyone was tired out.
The journey seemed to be quite twenty miles. The first thing we did
was to see the wounded safely into the hospital, which was a young
men's college. M. L'Abbé J. Lebrun, the Superior, and his colleague
were at the door to welcome us. I was at once taken into the English
ward, and arrived just in time to commend the soul of a dying man,
a private of the 12th Lancers. His officer—though wounded—had got
out of bed to see the last of him, and besought me as I entered to
visit his dying comrade without delay. His anxiety on his friend's
behalf was a touching sight.
On the morrow, Sunday, August 30, I held a service, at the request
of the patients, in the English ward. I spoke on "Be of good cheer,"
or, as we had so often heard it put by our French friends along the
road, "Bon courage."...
At the funeral of the 12th Lancer that afternoon we had an imposing
procession. The body was laid on a stretcher covered over with a
Union Jack and the French national flag. I led the way before the
coffin, robed in a cassock and surplice which had been presented to
me by a French priest to replace my own lost robes. After the coffin
came the three R.C. priests of the town and a number of the French
Red Cross nurses; then Major Collingwood and the men of the 4th
Field Ambulance. One of the nurses, noticing that I had no stole, on

returning from the funeral made me one of black material with three
white crosses, and presented it within a couple of hours.
The next day we were marched under escort to Mons. This is a
large, well-built town of about 35,000 inhabitants. We were paraded
through the cobbled streets to the barracks, then (evidently by a
mistake) to the station, and finally back again to the barracks,
where, in some dirty rooms over a filthy stable, we spent the night.
Here we met the Hon. Ivan Hay, of the 5th Lancers, who had
narrowly escaped being shot after his capture by the Germans, but
he was not allowed to accompany our party. The following morning
we were marched once more to the station, and were bundled into
the station-master's office, which was littered with looted papers.
The men meanwhile were herded in a shed. A sentry was posted at
the entrance of the station to prevent anyone going to the town.
Just outside the station were the ambulance wagons and our
servants. Whyman, my soldier-servant, was amongst them with my
horse. That was the last I saw of either of them. I parted from them
with a very sad heart.
During the afternoon an ill-mannered under-officer bade us hand
over knives, razors, and sticks. At 6 P.M. we were entrained with
about 1,000 wounded, of whom some forty or fifty were ours, the
rest being Germans. The train must have been a quarter of a mile
long. In the middle of the night we passed through Brussels, and in
the early morning through Louvain and Liège. Louvain seemed to be
a heap of ruins; hardly a house visible from the station was intact....
We looked with great interest upon Liège as we passed through it,
and recalled the gallant defence of the town by the Belgians. A few
more miles brought us over the border into Germany.
At Aachen a hostile demonstration took place at our expense. There
happened to be a German troop train in the station at the time. A
soldier of our escort displayed a specimen of the British soldier's
knife, holding it up with the marline-spike open, and declared that
this was the deadly instrument which British medical officers had
been using to gouge out the eyes of the wounded Germans who had

fallen into their vindictive hands! From the knife he pointed to the
medical officers sitting placidly in the train, as much as to say, "And
these are some of the culprits." This was too much for the German
soldiers. They strained like bloodhounds on the leash. "Out with
them!" said their irate colonel, pointing with his thumb over his
shoulder to the carriages in which these bloodthirsty British officers
sat. The colonel, however, did not wait to see his behest carried out,
and a very gentlemanly German subaltern quietly urged his men to
get back to their train and leave us alone. The only daggers that
pierced us were the eyes of a couple of priests, a few women and
boys, who appeared to be shocked beyond words that even a
clergyman was amongst such wicked men. The enormity of the
crimes which had necessitated my capture I could only conjecture
from their looks.
At Düsseldorf we crossed the Rhine—a beautiful sight. At Essen I
was permitted to visit one of our wounded men who was dying of
tetanus. The unfortunate patients lay in rows on the floor of luggage
vans, with straw beneath them. When the train stopped at a station
the doors of these vans were sometimes flung open in order that the
crowd might have a look at them....
Even the Red Cross ladies at the stations steeled their hearts against
us, giving us not so much as a cup of coffee or a piece of bread. But
for the haversack rations and chocolate, which most of us carried
with us, we should have fared badly. Now, however, we were to
receive our first meal from our captors. This consisted of a plate of
hot soup and a slice of bread and butter, which we ate ravenously.
Two kind ladies brought us this food, and we were duly grateful. One
of them was standing near me as we ate the meal, and I thanked
her cordially in English. She paid no attention, so I asked her if she
understood English. "I do, but I don't mean to," was her laconic
reply, which seemed highly to amuse my companions....
At length, on Friday morning, the journey came to an end on our
arrival at Torgau. We were ordered out of the train and drawn up on
the platform in fours. Each officer carried what articles of clothing he

possessed. Several of them had preserved their medical panniers,
and, heavy as these were, they had to be carried or left behind. On
either side of us a German guard with fixed bayonets was drawn up,
and then was given the word, "Quick march!" With our bundle on
our shoulder, there was no man could be bolder, yet this same
bundle and the burning sun prevented there being anything "quick"
about our march. The townsfolk evidently had heard that we were
coming, and they were at the station gate in scores to show us how
pleased they were to welcome us to their town. In fact, they told us
quite freely what they thought of us and the nation which we
represented. They walked beside us every inch of the way, keeping
up our spirits by telling us the particular kind of Schweinhunds they
believed the Engländer to be. Not until they had crossed the massive
bridge which spans the Elbe and reached the Brückenkopf fortress
did they turn back home, and the doors of the fortress closed behind
us.
IV—STORY OF PRISON LIFE AT TORGAU
Passing over the moat through two iron doors, we enter a courtyard,
about 100 yards long by 40 broad. Facing the gateway is a semi-
circular building two stories high, with an entrance at either end and
one in the centre. A turret with windows and battlements surmounts
each entrance; and from the central turret rises a flag-pole....
The commandant was a Prussian reservist officer with a long heavy
moustache. We were told that he was courteous and considerate in
every respect, and that, provided we took care to salute him
whenever we passed him, we should find him everything we could
reasonably wish.
Supper was at 6 P.M. The same plate did duty for both courses, soup
and meat, the more fastidious taking it under the pump in the
interval. When the meal was over the junior members of the messes
did the washing up. After supper we walked a mile, as the old adage
recommends. We soon knew to a nicety how many turns round the
court made up this distance, and some active spirits improved on the

advice by walking several miles. At 8.30 a bugle sounded, and
everyone had to retire to his room; at 9 sounded "lights out."
That first night was memorable for the little occupants which we
found already in possession of our beds. Just when we hoped we
had finished our labours for the day these little bedfellows began
theirs. The more we wanted to sleep, the more wakeful they
became. Scratching, tossing, and—it must be owned—a little mild
swearing could be heard, where snoring would have been much
more tolerable....
At 6 A.M. reveillé sounded, and before it was finished Major Yate
was up and out of bed. I followed his example, and then the two of
us began a practice which we kept up while the warm weather
lasted, namely, a cold bath under the pump in the solitude of the
courtyard.
Poor Major Yate! He attempted to escape ten days later, and lost his
life in so doing. One of the sentries affirmed that he shot him as he
made his way through the barbed wire, and that the Major fled
wounded into the river, from which he never came forth alive.... He
has since been awarded posthumously the Victoria Cross for his
gallantry in the campaign.
We selected as our chapel the passage over the entrance at one end
of the building. There was an inspiring atmosphere about that first
service. Our altar was a dormitory table, our altar linen a couple of
white handkerchiefs, our chalice a twopenny wine-glass (the best we
could procure), our paten an ordinary dinner-plate. Pews, of course,
there were none, and as for books, we were fortunate enough to
have one, a hymn-book, prayer-book, and Bible bound together in a
single volume, which I was carrying in my haversack at the time we
were captured. The pew difficulty was overcome by each officer
bringing his stool. The lack of books made no difference to the
heartiness of the service, for the hymns and chants were familiar to

most of us from childhood. The mighty volume of sound that went
up that morning in hymns of thankfulness and praise was a never-
to-be-forgotten sensation to those who heard it or joined in it. The
place whereon we stood was holy ground, and it was good for us to
be there....
As time went on, our numbers increased to about 230 British
officers, and 800 French officers joined us from Maubeuge, including
four generals. One of the latter had been interned in Torgau before,
in the 1870 war, and had made good his escape. The authorities
guarded against the recurrence of such an eventuality on the
present occasion, their most elaborate precaution being the
enlistment of dogs to reinforce the sentries. Their barkings could be
heard occasionally by night, but their presence disturbed neither our
repose nor our equanimity....
During the last two months of our stay at Torgau I occupied a small
room in the centre of the building with Major (now Lieut.-Col.) A. G.
Thompson, Major W. H. Long, and Captain P. C. T. Davy, of the
R.A.M.C., as companions. Like the Hindus, we divided ourselves into
exclusive castes, as far as the necessary duties in connection with
the room were concerned. The Colonel (as we may call him by
anticipation) lit the stove, the Major washed the cups and saucers,
the Captain swept the floor, and I, with the assistance of a member
of our mess, brought in the coal.
We often dreamt and spoke of the day when we should march out of
Torgau. There were two destinations only which came within the
range of our contemplation—one was Berlin, and the other was
England. Meanwhile, however, there was a place of four short letters
which was to be our home for six long months.
(The chaplain continues to relate his experiences in this German
prison with many interesting anecdotes. He tells about the prison
occupations, how they spent their time in work and recreation, and
describes his parole and visits to several internment camps.)

FOOTNOTE:
[9] All numerals relate to stories herein told—not to chapters from
original sources.

"AT SUVLA BAY"—THE WAR
AGAINST THE TURKS
Adventures on the Blue Aegean Shores
Told by John Hargrave, the Famous Scoutmaster in
the Mediterranean Expeditionary Forces
John Hargrave is known throughout England as "White Fox," the
famous scoutmaster. On September 8th, 1914, he said farewell
to his little camp in the beechwoods of Buckinghamshire and to
his woodcraft scouts and went off to enlist in the Royal Army
Medical Corps. He was assigned to the 32nd Field Ambulance, X
Division, Mediterranean Expeditionary Forces, and sailed away
to Suvla Bay, where he passed through the tragic scenes of the
Dardanelles Campaign. He soon began sending stories "back
home," achieving for the Gallipoli Campaign what Ian Hay did
for the Western Front. These stories have been collected into a
volume entitled: "At Suvla Bay," which is published in America
by Houghton, Mifflin and Company. There are twenty-eight
narratives told in the jargon of the common soldier. He tells
about its being "A Long Way to Tipperary"; "Mediterranean
Nights"; "Marooned on Lemnos Island"; "The Adventure of the
White Pack Mule"; "The Sniper of Pear-Tree Gulley"; "The
Adventure of the Lost Squads"; "Dug-Out Yarns"; "The
Sharpshooters"; and many other incidents of Army life. One of
his narratives, "Jhill-O! Johnnie!" is here retold by permission of
his publishers.
I—STORY OF THE INDIAN PACK MULE CORPS

One evening the colonel sent me from our dugout near the Salt Lake
to "A" Beach to make a report on the water supply which was
pumped ashore from the tank-boats. I trudged along the sandy
shore. At one spot I remember the carcass of a mule washed up by
the tide, the flesh rotted and sodden, and here and there a yellow
rib bursting through the skin. Its head floated in the water and
nodded to and fro with a most uncanny motion with every ripple of
the bay.
The wet season was coming on, and the chill winds went through
my khaki drill uniform. The sky was overcast, and the bay, generally
a kaleidoscope of Eastern blues and greens, was dull and gray.
At "A" Beach I examined the pipes and tanks of the water-supply
system and had a chat with the Australians who were in charge. I
drew a small plan, showing how the water was pumped from the
tanks afloat to the standing tank ashore, and suggested the
probable cause of the sand and dirt of which the C.O. complained.
This done I found our own ambulance water-cart just ready to
return to our camp with its nightly supply. Evening was giving place
to darkness, and soon the misty hills and the bay were enveloped in
starless gloom.
The traffic about "A" Beach was always congested. It reminded you
of the Bank and the Mansion House crush far away in London town.
Here were clanking water-carts, dozens of them waiting in their turn,
stamping mules and snorting horses; here were motor-transport
wagons with "W.D." in white on their gray sides; ambulance wagons
jolting slowly back to their respective units, sometimes full of
wounded, sometimes empty. Here all was bustle and noise.
Sergeants shouting and corporals cursing; transport-officers giving
directions; a party of New Zealand sharpshooters in scout hats and
leggings laughing and yarning; a patrol of the R.E.'s Telegraph
Section coming in after repairing the wires along the beach; or a
new batch of men, just arrived, falling in with new-looking kit-bags.

It was through this throng of seething khaki and transport traffic
that our water-cart jostled and pushed.
Often we had to pull up to let the Indian Pack-mule Corps pass, and
it was at one of these halts that I happened to come close to one of
these dusky soldiers waiting calmly by the side of his mules.
I wished I had some knowledge of Hindustani, and began to think
over any words he might recognize.
"You ever hear of Rabindranarth Tagore, Johnnie?" I asked him. The
name of the great writer came to mind.
He shook his head. "No, sergeant," he answered.
"Buddha, Johnnie?" His face gleamed and he showed his great white
teeth.
"No, Buddie."
"Mahomet, Johnnie?"
"Yes—me, Mahommedie," he said proudly.
"Gunga, Johnnie?" I asked, remembering the name of the sacred
river Ganges from Kipling's Kim.
"No Gunga, sa'b—Mahommedie, me."
"You go Benares, Johnnie?"
"No Benares."
"Mecca?"
"Mokka, yes; afterwards me go Mokka."
"After the war you going to Mokka, Johnnie?"
"Yes; Indee, France—here—Indee back again—then Mokka."
"You been to France, Johnnie?"
"Yes, sa'b."
"You know Kashmir, Johnnie?"

"Kashmir my house," he replied.
"You live in Kashmir?"
"Yes;—you go Indee, sergeant?"
"No, I've never been."
"No go Indee?"
"Not yet."
"Indee very good—English very good—Turk, finish!"
With a sudden jerk and a rattle of chains our water-cart mules pulled
out on the trail again and the ghostly figure with its well-folded
turban and gleaming white teeth was left behind.
II—HEROISM OF THE SILENT HINDUS
A beautifully calm race, the Hindus. They did wonderful work at
Suvla Bay. Up and down, up and down, hour after hour they worked
steadily on; taking up biscuits, bully-beef and ammunition to the
firing-line, and returning for more and still more. Day and night
these splendidly built Easterns kept up the supply.
I remember one man who had had his left leg blown off by shrapnel
sitting on a rock smoking a cigarette and great tears rolling down his
cheeks. But he said no word. Not a groan or a cry of pain.
They ate little, and said little. But they were always extraordinarily
polite and courteous to each other. They never neglected their
prayers, even under heavy shell fire.
Once, when we were moving from the Salt Lake to "C" Beach, Lala
Baba, the Indians moved all our equipment in their little two-
wheeled carts.
They were much amused and interested in our sergeant clerk, who
stood 6 feet 8 inches. They were joking and pointing to him in a little
bunch.
Going up to them, I pointed up to the sky, and then to the Sergeant,
saying: "Himalayas, Johnnie!"

They roared with laughter, and ever afterwards called him
"Himalayas."
THE INDIAN TRANSPORT TRAIN
(Across the bed of the Salt Lake every night from the Supply Depot
at Kangaroo Beach to the firing-line beyond Chocolate Hill,
September, 1915.)
The Indian whallahs go up to the hills;—
"Jhill-o! Johnnie, Jhill-o!"[10]
They pass by the spot where the gun-cotton kills;
They shiver and huddle—they feel the night chills;—
"Jhill-o! Johnnie, Jhill-o!"
With creaking and jingle of harness and pack;—
Where the moonlight is white and the shadows are
black,
They are climbing the winding and rocky mule-track;—
By the blessing of Allah he's more than one wife;—
He's forbidden the wine which encourages strife,
But you don't like the look of his dangerous knife;—
The picturesque whallah is dusky and spare;
A turban he wears with magnificent air,
But he chucks down his pack when it's time for his
prayer;—
When his moment arrives he'll be dropped in a hole;—

'Tis Kismet, he says, and beyond his control;
But the dear little houris will comfort his soul;—
The Indian whallahs go up to the hills;—
They pass by the spot where the gun-cotton kills;
But those who come down carry something that chills;
—
FOOTNOTE:
[10] "Jhill-o!"—Hindustani for "Gee-up"; used by the drivers of
the Indian Pack-mule Corps.

SEEING THE WAR THROUGH A
WOMAN'S EYES
Soul-Stirring Description of Scenes Among the Wounded in Paris
Told by (Name Suppressed)
I—"THEY HAVE NOTHING LEFT—NOT EVEN TEARS"
What I have seen—can that be told? When will words be found
simple enough and infinite enough to tell of so much heroism, so
much sorrow, so much beauty, so much terror? All those sublimities:
how can they be explained without losing their soul, without taking
away their value, which is of mystery and miracle? All those hideous
things, all those unnatural crimes; how can they be revealed with
cold and ponderous reasoning, while one is still trembling, keeping
back tears, smothering cries?
It must be done, though, and that French shyness that hates all that
is bluff or bragging, and which fain would wait that our glory and
suffering be understood, it too must be conquered. We must rise
above that too delicate conscience which says: "Speak? What good
will it do? Truth is luminous; it shines before all eyes." Yes, but it
must be helped to shine, and without delay.
That is why, I have decided to address the American nation, to tell it
that which I know, that which is evident, undeniable—to take it to
the frightful and divine Calvary of truth.
For six months I have been living among our soldiers, our wounded.
I live in my Paris. That Paris that every one visits and that no one
knows. I have only left it for some brief excursions to the cathedrals
in agony, to the villages in ashes, to the ambulances at the front, to

the old peasants who have nothing left—not even tears! To the little
orphans with tragic and stupefied eyes.
Sent to distribute woolens to the combatants, I have heard a
language, haughty and superb. I have clasped the rude hands,
sometimes deformed, of more than twenty-two thousand soldiers,
some wounded, others well again, returning to the firing line, a
flame in their eyes and in their hearts. I have bent over more than
ten thousand beds of mutilated young men, many of them with
gangrene. I have held hundreds in my arms on the operating tables
—I who could not support the sight of blood, nor of illness—
hundreds of poor things with atrocious wounds, and only felt during
those minutes one care—a superhuman desire to discover in the
surgeon's look or attitude the hope the poor boy would be saved.
II—"IF HE DIED, I SHOULD HAVE FELT GUILTY"
I remember, above all, a youth twenty years old, who had such a
complicated wound in the chest that it is indescribable. I held the
poor, inert body while the surgeon lay wide open the thorax. "Take
him back," said the surgeon, "and be careful." I did so. Then from
the deep, bleeding wound the whole chest emptied itself, as one
empties a bucket of I don't know what unnamable liquid. The
surgeon approached then, and leaning over the now visible
palpitating lung murmured: "What can be done? It will only begin
again." However, he did find out what could be done. He had him
put back in his bed—he was still unconscious. Sitting near him, filled
with anxiety I waited his awakening. I wanted him to be saved, that
child! While he was being chloroformed a few minutes before, while
he was holding my hand without saying a word, there was in his
look, before his eyes closed, such a gentle desire to live, such a
prayer for protection—such confidence in the infinite aid I gave him.
If he died I should have felt myself guilty—I don't know of what.
He awoke—looked at me and smiled. He then murmured: "Why are
you so good to us, madame? We are not near to you."

To this dying child, to give him back his life, it was necessary I
should explain to him his glory. I said: "Not near, my boy? Why,
understand then what I owe you! If the enemy has not entered our
Paris—if Notre Dame is intact—if I, myself, am living—it is because
you gave your blood for us. But that is not all. When you fight for
France you do not only fight for your country, you do not only save
your native land; you save an ideal, an ideal supreme, universal. In
helping all that is pure and beautiful in the world you save the liberty
of peoples, the liberty of the soul. You say to each one of us 'the
yoke that weighs you down I shall help you to cast off.'
"You do not understand me well, my boy. But see—you must live.
Later in the eternal books of history you will learn the meaning of
the blood you have given. You must live! You must live! Years from
now your little children will look at you with eyes of love and
admiration because you were a soldier in the great war. They will
know the meaning of the medal shining on your chest, and for
generations they will be proud of the honour of their name. You
must live, my dear boy!"
As I spoke something wonderful illuminated the youth's eyes. "Oh, I
shall live, madame. One only has to will it. I shall live."
He is saved!
I do not know why I stopped to recount the agony and resurrection
of that child, because almost all of them are divinely alike—childlike,
confident, smiling.
Another had had a whole leg amputated—a young man of twenty-
two, with a charming face. Doubtless he had already been loved by
some pretty girl. At last the day came when for the first time he was
to get out of bed and try to walk with crutches. I dreaded that
moment. I expected complaints. I already had made up my
consoling arguments.
Ah, how little I knew the soul of our children of France. He arose,
poor boy, so thin, on his one leg; and as he was also wounded in

one arm, in spite of the crutches he couldn't balance himself. That
made him laugh; made him laugh!
I turned him over to a nurse because tears were choking me. But
they were not tears of sorrow; they were sobs of tenderness,
respect, admiration.
Another had received nine wounds. He didn't want to have them
spoken of. He only wanted to talk about his days of battle—to live
them over again. "Those last days, madame, we were so near the
enemy that they could not get to us to bring us our rations. We had
to find our nourishment ourselves. When evening arrived some of us
would steal out of the trenches and pick carrots—we lived eleven
days like that. One day I brought down a pigeon. When I was able
to get it we broiled it with matches. Ah, that was a royal feast! How
glad we were!"
"Content" (glad, happy), that was the word he used most frequently.
One morning when I got to the hospital, believing him still very ill,
he greeted me with, "I go back to my depot in three days; in a
fortnight I shall be under fire! Oh, how 'content' I am!"
Since then he has written me, "I received the tobacco. We had an
awful fight at ——. I have a finger less and am still in the
ambulance, but still 'content.'"
III—STORY OF THE DYING ALGERIAN
Ah, let me still tell of my country's smile in her sorrow—so sweet,
and which is such a comfort to my heart. I have so much to tell that
is horrible.
Another time I conducted a celebrated visitor to a "tirailleur" (a part
of the colonial infantry who leave the ranks in action and fight
individually). This "tirailleur" had had his right arm amputated. I
said, "he is an Algerian." The wounded man looked at me
reproachfully with his great soft eyes, saying: "Don't say Algerian,
madame, me French, me give arm for France."

Another time I was with another Algerian; this one was about to die;
nothing could save him. I was trying to soften his agony. He let me
go on awhile, then suddenly stopped me with the melancholy
childish accent of the Arabs, saying: "Don't bother about me any
more, madame. All over. Me dead in two hours. Me just as happy as
if get well. Thee write my mother that." I wrote his mother. She
replied: "He has served France well. Allah has taken him to his
breast."
IV—"WHAT I HAVE SEEN IN PARIS"
What I have seen! I have seen Paris under the Teutonic shadow cast
from the north. Three days, on opening my windows at dawn, I
anxiously listened for the expected rumble of the cannonading.
Nothing.... It will be soon, this evening, to-morrow, I said.
Everything in my threatened city became sacred to me. For me to
die, that was nothing. But for Paris to be destroyed; my Paris! the
city that cannot be described; cannot be explained! I couldn't stand
that. I burst out weeping in the deserted streets, leaning perchance
against a humble and old house. This mere relic had feelings,
regrets, like the most sublime monuments.
The gravest day dawned. Those who only stayed in Paris for the
pleasure they receive from it, and those who have children to take
care of, were hastening toward the stations or crowding into
automobiles. I stayed there. My heart wrung with agony, I drifted
through my ordinary occupations. Then the unbelievable happened.
As I was crossing the Place de la Madeleine, in a semi-dazed
condition, a little boy, about five or six years old, ran up to me and
gave me a slip of paper. I saw distractedly that he was decently
dressed and had large blue eyes. I automatically opened the paper.
The following unheard of phrase was typewritten on it: "France is
invincible."
I turned toward the child: "Who gave you that?"
"Madame," said the little one, raising his head with a look that was
grand, immense, "We wrote them ourselves, all night." Tears filled

my eyes; I had a presentiment they were tears of deliverance. So,
while we knew the Uhlans were in Chantilly, while in the hearts of
the grown-up people horror placed its claws on faith, on hope, there
was a little child with immense blue eyes, who knew nothing, like
the good shepherds, St. Genevieve and Joan of Arc, but who knew
that "France was invincible" and who passed the night writing it.
Yes, the miracle that saved Paris was revealed to us. But there was
another miracle, something imponderable, which was the soul of the
little boy with his eyes of light—which is the soul of Paris.
Paris ... even during those hours did not lose its sweet disposition of
smiling independence. And it was among the children that we found
the most touching proofs. One day—at the hour when the German
aviators were storming Paris with bombs—we called it our five
o'clock taube—I went out with a friend near the Park Monceau. All
the passers-by were walking with their noses in the air, as they
already had got the habit of the visits of "the bad pigeons."
One little boy had his bicycle to follow the flight, another a pair of
opera glasses. But look around in the sky as I might, I could see
nothing. Then a little boy, this one about six or seven years old,
pulled my coat. "Straight up, madame; straight up, over my head!"
That's how they frightened our little kiddies!
The next day I was passing through a thickly populated
neighbourhood over which they had been flying for an hour.
Suddenly a child bolted out of a house as fast as it could go. But his
mother caught him and administered two resounding slaps. "I told
you to stay in the house." "Ah," protested the urchin, "ye don't only
keep me from seein' de tobe, but cher lick me in der bargain."
These are trifles, will perhaps be said. Do you think so? Nothing is
small that reveals the immortal soul of a people. And we found it so
everywhere. Don't lose patience with me if I speak without order. My
words resemble the days I am living. They have a unity, however, as
from them always shines forth the trials, the smiles, the bravery of
my country.

V—"THEY ARE ALL DEAD NOW"
What have I seen?... I saw a white glove stained with a gray spot
and a brown spot. Here is its history. When war was declared all the
young students of the Saint Cyr Army School were promoted second
lieutenants. Their average age was about twenty years. How happy
they were to fight for France. But to fight was not enough. They
must do it with grace, with style, carelessly, according to French
traditions. They all swore, those boys, to go to the first battle
wearing white gloves. They kept their word. But the white gloves
made them a mark for the ambushed sharpshooters. They are all
dead. The glove I saw belonged to one of them. The gray spot is of
brain—the brown spot is blood. Piously this relic was brought to the
mother of the dead young man. This special one was only nineteen
years old.
And let us not think that it was a useless sacrifice. It is well that in
the beginning of this war of surprises, mud and shadow, some of our
children died in the light, facing the enemy, and facing the sun, for
the good renown of French allegiance.
What I have seen ... Yesterday I received a letter. It came from a
sergeant in the Argonne, an uneducated workman. Here it is, with
the spelling and punctuation corrected:
"Madame, thanks for letting me know that my wife has had a little
girl. But do not think I am worried. We love our families, but our
duty is to love our country first. And if I do, those at home will be
taken care of, I know it, madame.
"I'm going to tell you something you'll be glad to hear, not at the
beginning, but you'll see at the end. A couple of weeks ago we lost a
trench and almost everybody was massacred, including our
commander. I escaped with a few more of my men. From our new
trench we could see the bodies of our comrades and officers down

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