1. The Application of Disposable Single Use
Equipment, and it’s impact on Biopharma
Plant Design
By Andy Rayner
PM Group, Group Director of Technology
2. Agenda
• Acknowledgements
• Organisations developing standards and
guidelines for equipment use
• Typical Manufacturing Implementations
• Available Single Use Equipment for Cell Culture
• Some implementation issues
• Impact of single use equipment on plant design
• Impact on Capital Investment and Cost of Goods
• Advantages and Disadvantages of Single Use
Equipment
3. Acknowledgements
The information in this presentation is generated from experience of use of disposables
on a number of past projects.
In particular I would like to acknowledge Elan for their permission to share the results of
their work on Project Iomlán.
The Iomlán team members who contributed to the disposables aspect of the project
included team members from:
- Elan
- PM Group
- Biopharm Services
- CRB
I appreciate their contribution and their kind permissions in generating this presentation.
4. Organisations developing standards
• BPSA Bioprocess
Systems Alliance
• ASME BPE
Polymers Sub-
committee
• PDA Single Use
Taskforce
• ISPE Disposables
Community of
Practice
Diagram by Jerry Martin Pall Life Sciences, Chairman BPSA
7. Second Stage Disposables Implementation
Available – Good Application
Available. but must confirm process suitability
Available. but must confirm process suitability
Unavailable at larger scales
10. Scale of Operations
100,000L
25,000L
Stainless Steel Envelope
Fully Dedicated Facilites
10,000L
(500Kg to 3,000Kg)
2,000L
Concurrent Multi-Product
1,000L
Facilites (10Kg to 1000Kg)
Clinical Production Facilites
(2Kg to 30Kg)
100L
10L
Disposables Envelope
10Kg 100Kg 1,000Kg 3,000Kg
Source: Based upon initial concept by Jagschies, GE Healthcare, Bioprocess International 2007
11. Some Implementation Issues
• Bag Design
• Pay attention to the design of the bag – the process
is yours not the vendors
• Consider producing P&ID sketches of each bag to
illustrate what you want – for enquiry to the
vendor(s)
• These should show the connections and fittings that
you want to standardise on – not necessarily the
ones the vendor(s) want to sell you
• Bag Material of Construction (MOC)
• Consists of a multlayered plastic
• each layer is a different material
• Product contact layer MOC depends on the supplier
• PolyEthylene (PE)
• Low Density PolyEthylene (LDPE)
• Ultra Low Density PolyEthylene (ULDPE)
• Ethylene Vinyl Acetate (EVA)
12. Standard vs Bespoke Designs
• Vendors offer standard and bespoke bag configurations
• Careful consideration should be given to every bespoke bag configuration
• Delivery time for each bag is longer (typically 9-15 weeks)
• Cost of each bag is greater – due to initial design time and bespoke production run
• Prototyping with the first bag is recommended – involves a longer timeframe
• Delivery of first bag
• Prototype Test
• Modify design (if necessary)
• Delivery of final bag
13. Pilot Plant Studies
• Decide early on what development work is required to ensure you can
demonstrate a sound understanding of the process
• There are published studies showing the performance of the bag systems
versus conventional systems – review these and risk assess which
equipment require additional pilot plant studies with placebo or product
• Consider how new the equipment item is to the market in terms of technology
and scale of implementation envisaged – most of the technology is relatively
new
• Complex items such as bioreactors are likely to require pilot plant work
upfront to confirm the parameters and performance of the system – if these
have not been done then consider the impact of these on cost and timeline
14. Procurement Considerations
• Involve procurement personnel from an early stage
• Seek to procure both the capital equipment and the ongoing supply of consumables
contract at the same time for leverage reasons
• Consider carefully the security of the supply chain
• How many sites manufacture the bags?
• Can alternative suppliers provide the same bag?
• Carefully consider the prequalification strategy
• Risk assess the equipment items to determine extent of prequalification
• What is the risk to the process?
• How much of the equipment is bespoke?
• How complex is the equipment?
• How many suppliers could provide the equipment?
• How large is the capital investment?
16. Leachable & Extractable Studies
• Solvents (including water) will extract materials from the bags and tubing over time
• A leachable and extractable study will determine what and how much of each
component could be extracted over time for different concentrations and conditions
(e.g: pH, temperature, etc..)
• Extractables Study
• An extractables study is a study to determine what potentially could be extracted from the
bag. It uses solvent systems with extreme solubility parameters at extreme time and
temperature to extract all possible components at their maximum concentrations to
facilitate ID
• Leachables Study
• Quantitative analysis of material (from list of extractables) that migrate into product /
solvent / buffer stored in bags at time / temp used in production
• Vendors have many typical solutions already studied for their products
• As part of the design and validation activities a risk assessment should be undertaken
utilising the vendor data, comparing against process conditions to determine whether
any additional studies are required
18. Disposables reduce facility size and
water usage
• Room sizes for production generally smaller
• Tends to be less platforming as equipment generally tends to be
smaller/shorter
• As equipment is often mobile it can be placed closer together, whilst still
allowing access for maintenance
• CIP/SIP requirements removed/reduced
• Remove footprint of CIP skids
• Removes the complexity of pipework associated with CIP/SIP
• Space for technical chases less relevant as density of piping has decreased
• Less CIP/SIP operations means:
• Potentially much smaller water (WFI) usage and Purified Water (PW) usage
• Smaller WFI still, smaller distribution tanks, smaller WFI loop sizes
• Smaller purified water generation system
• Smaller chemicals usage
• Smaller usage of Caustic and Acid Solutions for CIP
• Less steam usage in production areas
• Reduces water usage
• Reduces hazards due to heat
19. Typical Large Scale Cell Culture Facility
Potential Impact on Overall Site Utilities
POWER WATER GAS POWER WATER GAS
4.2 MVA 720 M3/DAY 1,010 NM3/HR 1.9 MVA 64 M3/DAY 160 NM3/HR
2 x 15,000L bioreactors 12 x 2,000L disposable bioreactors
Incl. USP + DSP Incl. USP + DSP
1 x 1,000L Pilot Plant 1 x 1,000L Pilot Plant
Labs, Admin, CUB Labs, Admin, CUB
Site Infrastructure Site Infrastructure
WASTE WATER SOLID WASTE WASTE WATER SOLID WASTE
631 M3/DAY <200 TONNE/YR 54 M3/DAY <200 TONNE/YR
This shows that extensive use of disposables improves sustainable design by significantly reducing site utilities
Thanks to Elan Pharmaceuticals for kind permission to use this data generated by PM Group
20. Transfer between rooms
PLAN VIEW ELEVATION
Buffer Hold Room
BUFFER HOLD PURIFICATION ROOM
Chromatography
Skid
Purification Room
21. Tubing transfers between rooms
• Establish Room HVAC Classifications
• Between rooms of the same grade
• Between rooms of different grade
• Establish Containment requirements
• Biosafety classification of each room
• Chemical containment classification
• Open vs Closed Processing in each room
• Number of transfers to take place
• Establish the total number of room to room transfers
to take place and the size of each transfer line
• Only then select the transfer technology
• Transfer Hatch
• Rat Hole
• Iris
• RAFT
22. Building Stacking Concepts - Horizontal
HVAC
Utilities Media Preparation & Cell Culture & Support Purification & Buffer Preparation & Warehouse
Media Hold Harvest Bulk Fill Buffer Hold
Horizontal Production Concept 1
HVAC
Media Preparation & Cell Culture & Support Purification & Buffer Preparation &
Media Hold Harvest Bulk Fill Buffer Hold
Utilities Support Utilities Warehouse
Horizontal Production Concept 2
Both allow ease of material & personnel access to all production rooms without the use of stairs or
elevators
Avoids the transfer of tubing between floors
Suitable for Single Use (Disposables) and small scale stainless steel facilities
23. Building Stacking Concepts - Vertical
HVAC
Media Preparation & Support Buffer Preparation &
Media Hold Buffer Hold
Utilities Cell Culture & Support Purification & Warehouse
Harvest Bulk Fill
Vertical Production Concept 1
HVAC
Media Preparation & Support Buffer Preparation &
Media Hold Buffer Hold
Cell Culture & Support Purification &
Harvest Bulk Fill
Utilities Support Warehouse
Vertical Production Concept 2
HVAC
Media Preparation & Support Buffer Preparation &
Media Hold Buffer Hold
Cell Culture Support Purification
Harvest Support Purification &
Bulk Fill
Utilities Support Warehouse
Vertical Production Concept 3
Not for disposables, More suited to large scale stainless steel vessels
24. Production all at one level
Thanks to Elan Pharmaceuticals for kind permission to use this image created by PM Group
25. Logistics
• Single Use (Disposable) facilities will result in
more materials handling
• Components (bags, filters, tubing, etc…)
• Movement of buffers and media to point of consumption
• Movement of raw materials to media and buffer prep
• It is important to consider how the plant will be
operated
• Operation of a facility utilising significant quantities of
disposable equipment is more akin to a discrete
manufacturing operation
• Lean manufacturing concepts can play an important role
26. Lean manufacturing
Important Concepts for single use (disposables) facilities
• 5S – Sort, Set In Order, Shine, Standardize, Sustain
• Be organised, everything has it’s place
• 7 (now 8) Wastes
• Overproduction, Waiting, Transportation, Inventory, Motion (non value added),
Over Processing, Rework, (Talent)
• Takt Time
• The “heartbeat” of the facility, used to standardise production time of workcells for
line balancing
• Mistake Proofing (Poke Yoke)
• Ensuring that the wrong connection is not made, or wrong bag assembly is not
used
• Line Side Warehousing
• “Pull” system to Kanban supermarkets in place of pushing to inventory
27. Ergonomics
• Ergonomic Reviews are also vitally important to
undertake, consider for example:
• The increased number of manual manipulations and the
location of the manipulations (eg: does the operator have
to stoop down to make a connection?)
• The maximum weight of mobile disposable equipment
which can be moved by 1 person (with power assist)
• The maximum weight of mobile disposable equipment
which can be moved by 1 person (with power assist)
28. Instrumentation
• Decide if the instrumentation should also be Single Use
(Disposable)
• The ability exists to insert conventional probes into single use bags
• Single use instrumentation is available for applications including:
• pH and Temperature probes
• Dissolved Oxygen (DO) and Temperature probes
• Pressure Transmitters
• Probes available pre-calibrated and pre-inserted
• depending upon bag suppliers and contract arrangements
• Tracking of Probes either by bar coding or by utilising Radio
Frequency Identification (RFID) tagging in probe which can:
• Hold calibration Information
• Provide Lot Traceability Information
29. Automation
• Each piece of equipment generally as standard has it’s own control
system often known as “Islands of automation”
• Without CIP / SIP is there a need for a controlling Distributed
Control System (DCS) ? All that remains is:
• Product Transfers between the “Islands of Automation”
• Utility Generation and Distribution
• Waste Treatment
• Alternative approach is to utilise a Manufacturing Execution System
(MES) rather than a DCS, an MES can provide features such as:
• Handle batch tracking and batch reporting
• Handle bar coding of components and bags
• Provide Electronic Work Instructions (EWI’s)
• Provide ability to view Standard Operating Procedures (SOPs)
• Data transfer to/from ERP systems (such as SAP)
30. Regulators Opinion of Disposables
• Disposables is an evolving technology
• “…There is no prohibition in the regulations against the manufacturing of drug
products using better, more efficient and innovative methods. In fact the
commissioner encourages the use of such as it benefits the consumer.” Nicholas
Buhay, Deputy Director FDA CDER DMPQ – “Regulatory Considerations for
Disposable Technologies- IBC Single Use Conference June 2008”
• Highlighted FDA Presentations
• Nicholas Buhay, Deputy Director FDA CDER DMPQ
• IVT Disposables Conference, Washington DC 02/07
• IBC Single Use Conference, La Jolla, CA 05/07
• J.David Dolesky, Reviewer, FDA, CBER DMPQ
• “Biological Process Risk Based Assessments: Biotech Process Validation
and the Use of Disposable Technologies” GMP by the Sea Conference,
Cambridge, MD, 08/07
• “Use of disposable technologies in Biological Products” PDA Pharmaceutical
Microbiology Conference, Bethesda, MD, 08/07 and ISPE Tampa Seminars,
Tampa, Florida 02/08
Ref: Jerry Martin presentation to ISPE Tampa Conference Disposables Track March 2009
31. Regulators Opinion of Disposables
• Challenges of disposables highlighted by FDA include:
• Irridation effect on materials
• Moisture and air permeation issues
• Maintaining sterility assurance - complex assemblies may lead to potential for leaks
• Process Knowledge and understanding – possible dependence upon outside vendor for
critical process equipment
• Potential impact of changes in polymer production or product availability on production
scheduling
• Due diligence in defining fitness for use criteria and inventory control for continuous supply
• Biocompatability and Leachable/Extractable issues
• Potential toxicity, carcinogenicity and/or immunogenicity
• Potential introduction of substances with poorly characterised physiochemical and
toxicological profiles
• Potential impact on product and product stability
• Equipment suitability for use – including ability to withstand process conditions, such as the
low temperature impact of freezing on bags
• To date 483’s relating to disposables include:
• Lack of written procedure for tubing connection
• Items for lack of qualification of process equipment and utility equipment
• Items for inadequate cleaning/validation of cleaning
Ref: Jerry Martin presentation to ISPE Tampa Conference Disposables Track March 2009
32. Impact on the project capital cost of
disposables
• Cost impacts in our experience on conventional versus disposable
facility large scale cell culture projects so far:
• Capital cost of equipment – disposables are cheaper
• On a western cost basis
• Facility size (including labs/admin/warehousing/utilities/ production) is 75%
to 100% of size for a conventional large scale cell culture facility depending
upon:
• Scale of production equipment
• Extent of disposables implemented
• Facility room layout and building configuration chosen
• Facility standard of finish chosen
• Extent of facility that is greenfield –vs- retrofit
• Most projects today remain hybrids – utilising some disposables and some
conventional stainless steel equipment
33. Impact on overall project schedule
• Schedule impacts in our experience on conventional versus disposable
facility large scale cell culture projects so far:
• Three key items will reduce the project schedule
• Equipment deliveries are faster
• Facility size is smaller
• The building and process is simpler
• Projects are faster from start of design to commercial manufacture
• Large Scale Cell culture projects with significant disposables implementation can
take 2-4 years
• Traditional Large Scale Cell Culture Projects using stainless steel typically take 3-
5 years
• This has some significant impacts
• The duration of time before manufacture is reduced – this reduces items such as
end user project team staff costs – but the end user must be ready quicker
• The decision to invest can be delayed (particularly important if the product driving
the business case is still in clinical trials, good to wait as long as possible)
34. Impact on Cost of Goods (COG)
• When evaluating a disposables project always consider the Cost of Goods as part of the
evaluation
• Software Tools exist to generate the Cost of Goods scenarios
• Consider the stainless steel case versus the disposables case
• Consider the variations in cost from different disposable equipment vendors products
• Principle drivers of the quantum of the differences are project specific and depend upon:
• Production parameters (such as scale, titre and yields)
• Operational parameters (such as equipment utilisation, operational philosophies and no’s of staff)
• Increase in operating cost for use of bags in terms of both their use and the disposal of same
• Savings in water usage and chemical usage
• Savings in capital cost
• Savings in project schedule
• Savings in production time (faster product changeovers)
• Reductions in Cost of Goods can be (typically) 5% to 20% depending upon the factors
above
35. Summary of Disposables Pro’s & Con’s
Traditional Stainless Steel
Technology Disposables Technology
Technical
- Product Changover Time Slower Faster
- Flexibility to change Painful Easy
- Campaign Turnaround Times Slower Faster
- Water Usage / Waste Water High Low
- Solid Waste Disposal Less More
- Leechable/Extractable Validation Small High
- Facility Size Larger Smaller
- CIP Complex Simpler
- SIP Complex Simpler
- Sustainability design Low High
Capital Cost & Cost of Goods USA/Europe Asia USA/Europe Asia
- Equipment Cost High Medium Medium Medium
- Facility Cost High Low Medium Low
- Cost of Goods High Medium Medium Medium
- Supply Chain Solid ok Solid ok
Expanded from an original concept in a table by Johannes Roebers, Senior Vice President,
Biologic Strategy, Planning and Operation in Elan Pharma International Limited, presented
initially to a PDA meeting in Dublin, Ireland in a paper entitled “Future Trends in
Biopharmaceutical Manufacturing” and dated 25th June 2008
36. Thanks – Any questions?
Contact details:
Andy Rayner
Group Director of Technology
PM Group
Killakee House,
Belgard Square,
Tallaght
Dublin 24,
Ireland
Tel: +353-1-4040700
Cellphone: +353-87-2858296
E-Mail: andy.rayner@pmg.ie
