Single Use Technology A Practical Guide to Design and

Implementation, 1st Edition

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Contents
Preface V

1 Introduction 1
1.1 Benefits and limitations of single-use technology 4
1.1.1 Improved process flexibility 4
1.1.2 Increased speed of implementation 4
1.1.3 Cost savings 5
1.1.4 Increased product safety 5
1.1.5 Technical limitations 6
1.1.6 Cost increases 6
1.1.7 Increased complexity 6
1.1.8 Dependence on suppliers 7
References 7

2 Strategies for implementation of single-use technology: A risk- and

science-based approach 9
2.1 A risk- and science-based approach 11
2.2 Implementation plan 14
2.3 Risk-assessment tools to support implementation 17
References 18

3 Feasibility assessment of single-use technology and suppliers 19

3.1 Technical feasibility 19
3.2 Business assessment 25
3.3 Selection of a supplier of single-use technology 33
References 38

4 Specifications and design of single-use technology 39

4.1 Framework for the design project 40
4.2 Design choices and risk 43
4.3 Specification 47
4.4 Design verification 49
References 50

5 Validation 53
5.1 Qualification of materials and assemblies 54
5.1.1 Integrity 57
5.1.2 Compatibiliy 57
5.1.3 Sterility and cleanliness 57
5.2 Process qualification 58
VIII Contents

5.2.1 Installation qualification and operational qualification – Water

or buffer runs 60
5.2.2 Process simulation – Media fills 61
5.2.3 Performance qualification – API stream 61
5.3 Continuous improvement of processes 62
References 63

6 Case studies 65
6.1 Case study 1: Single-use bag systems 66
6.1.1 Material selection 66
6.1.2 Risk assessment for extractables and leachables 68
6.1.3 Profiles of extractables and leachables 70
6.1.4 Specification and design 73
6.1.5 Qualification of final bag assembly 77
6.2 Case study 2: Single-use bioreactor 83
6.2.1 Selection of single-use bioreactor technology 84
6.2.2 Specification and design of single-use bioreactors 88
6.2.3 Risk assessment of the single-use bioreactor process 101
6.2.4 Qualification of single-use bioreactors 101
6.3 Case study 3: Tangential-flow filtration 104
6.3.1 Selection of technology for tangential-flow filtration 105
6.3.2 Specification and design 107
6.3.3 Risk assessment to support design of a system 115
6.4 Case study 4: Formulation and fill-finish 124
6.4.1 Selection of fill-finish technology 125
6.4.2 Risk assessment of fill-finish 125
6.4.3 Qualification of fill-finish operations 128
References 133

Abbreviations 135

Appendix 1 Scoring Tables 137

Appendix 2 Risk Rating and Priority Number 139

Index 141
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 achieve-
ments 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 technolo-
gies (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 de-
signed, 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 pro-
cess 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 technol-
ogies 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 knowl-
edge, availability and adaptability of the technology. There are no standardised ap-
proaches 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 con-
sidered 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

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Table 1.1: Risks involved in adoption and use of SUT.

End-user risks Supplier risks Material risks Process impact

Capabilities Business continuity Material qualification Quality

– Materials and logistics – Capacity – Product compatibility and extractables – Purity
– Stock management – Single sourcing – Migrants and leachables – Contaminant profile
– Dual sourcing – Disaster recovery – Bioburden/sterility – Product variants
1 Introduction

– Bill of materials complexity – Business continuity – Particulates – Location within process

Knowledge of SUT plans – Animal-free components
– Experience and understanding of SUT – Sterilisation Process performance
Supplier quality
– Operator training – Titre
– Audit Material complexity
– Standardisation – Yield
– Change control and – Compendial chemicals
– Testing new systems – Throughput
end-user notification – Integrated systems (standardisation,
– Selection methodology – Control requirements
– Transparency and dimensions, volumes)
– Relationship with SUT supplier compl- exity of the – Integration with equipment hardware
supply chain Facility fit
Knowledge of process Material integrity – Available equipment
– Understanding of the process/product Technical capability – Lot-to-lot consistency – Scale
– Scale of operation – Understanding of the – Containment and integrity against leaks – Local regulations
– Equipment experience process/product – Support utilities required
– Applications Handling
Quality – Warehouse requirements
development – Accumulation of particulates, endotoxin
– Supplier qualification – Flow of materials into
and bioburden contaminants
– Testing materials and release process – Service and support and within the facility
– Cleaning, disposal
– Change control management – Batch packing of
– Transport and storage
consumables and
materials
 1 Introduction 3

‘hybrid’ approach whereby implementation of SUT is used to support process oper-

ations 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.
There are many similarities between a project to implement a SUT and the tradi-
tional 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 appli-
cation, 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 implemen-
tation 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,

Feasibility Selection Implementation

Identify and SUT Finalise design

review specification
available SUT and design

Procurement

Supplier Supplier
review audit Qualification

Launch

Figure 1.1: Key focus areas during SUT implementation.

4 1 Introduction

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 pur-
pose 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.

1.1 Benefits and limitations of single-use technology

As the biopharmaceutical industry matures, the trends are towards the higher flexi-
bility 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 facil-
ity to meet changes in product scale or the type and number of products to be manu-
factured. 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 genera-
tion 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 flexibil-
ity, 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
 1.1 Benefits and limitations of single-use technology 5

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 impact-
ing 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 proce-
dures, as well as the equipment maintenance associated with these practices [4]. Re-
duction 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, genera-
tion 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, in-
crease the risk associated with cleaning procedures. SUT systems are used only
once for a specific process and operate in a closed-system environment, which pre-
vents 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.
6 1 Introduction

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 recom-
mended if they are likely to come into contact with organic solutions, or in opera-
tions 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 differ-
ent system designs and configurations. Sometimes, unconventional and unproven
scale-up/down methodologies must be considered [7]. Finally, the process perfor-
mance of a SUT system may not have been proven completely compared with the
traditional stainless-steel equipment it is intended to replace. Main concerns in-
volve 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 con-
sumables 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 rede-
signed 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 par-
ticular 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
 References 7

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 extract-
ables, where standard methodology is lacking [10].
Complexity can also arise from the tubing arrangements, assembly and disas-
sembly of single-use components, operation of sterile connections between equip-
ment 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 re-
stricted interconnectivity between different technology/suppliers places consider-
able 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 con-
siderations 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.
8 1 Introduction

[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 Table 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 reli-
ability 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 applica-
tion, 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 imple-
mentation 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 con-
cepts 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 suc-
cessful 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 ap-
proach, 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.

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 10

Feasibility Selection Implementation

Feasibile options Capital Ready for use

exits to proceed Sanction
Implementation Plan (Section 2.2) Trial (Section 3.1)⁎ Finalise Design (Chapter 4)
∙ Scope of implementation ∙ Hands-on trial with technology at required scale, ∙ URS, process and SUT component drawings
∙ Application (R&D, GMP, lab, pilot, etc.) either on-site or at suppliers facility ∙ BOM, Equipment list
∙ Project plan broken down by phases ∙ Test under process conditions /model system ∙ Testing plan and validation protocols
∙ Team & responsibilities
Concept Design (Chapter 4) Material Qualification (Section 5.1)
∙ Quality activities
∙ URS, process and SUT component drawings ∙ Leachable assessments where applicable
Technical (Section 3.1) ∙ Preliminary equipment list ∙ Integrity
∙ Manufacturing strategy ∙ Selection of preferred technology ∙ Compatibility
∙ Determine key process or oprerational ∙ Materials (BOM) and equipmnet list ∙ Sterility and cleanliness
requirements ∙ Warehouse and logistical controls
Qualification and validation (Chapter 5)⁎
∙ Identify specific SUT that will respond to ∙ Flow of materials and waste within facility
requirements ∙ Equipment FAT, SAT and QA approval
∙ Capital cost
∙ Installation & operational qualification
∙ Identify Key staff that will be using the ∙ Operational cost forecast
technology and who will be required to ∙ Maintenance and calibration documentation
∙ Technical and quality risk assessment
implement it successfully and frequency
Supplier review (Section 3.3) ∙ Staff training
Business case (section 3.2) ∙ Supplier risk assessment ∙ Generation of manufacturing documentation
∙ Business drivers ∙ Supplier audit ∙ Operator and QC training
∙ SWOT assessment ∙ Supplier management strategy, draft supply chain ∙ Performance qualification
∙ Capital and operational cost implication vs. & quality agreements
Launch (Section 5.3)
2 Strategies for implementation of single-use technology

alternative options such as stainless steel or ∙ Identify possible dual source supplier/technology
existing facility capabilities ∙ Complete qualification of suppliers
∙ Impact upon facility and existing operations Single-use Extractable Review (Section 5.2)⁎ ∙ Finalise & execute supply chain & quality
∙ Quality and logistical implications ∙ Extractable risk assessment agreements
∙ Review extractable data package where available ∙ Approval of all qualification documentation
Supplier assessment (section 3.3) ∙ Write material specifications
∙ Review available suppliers Update Implementation plan ∙ Build consumable stock for launch
∙ Supplier questionnaires
∙Case studies presented in Chapter 6

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, weak-
ness, opportunities and threats analysis; and URS: user requirements specification.
 2.1 A risk- and science-based approach 11

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 technol-
ogy works as intended and does not impact upon the active pharmaceutical ingredi-
ent (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 pro-
grams. . .’ and state that ‘quality should be built into the product’ from the develop-
ment 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 require-
ments. 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 compli-
ance; 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 de-
rived from material/human failure or a lack of knowledge of working with such