The Application of Disposable Single Use Equipment, and it’s impact on Biopharma

Plant DesignBy Andy Rayner

PM Group, Group Director of Technology

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

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.

Organisations developing standards

• BPSA Bioprocess Systems Alliance

• ASME BPEPolymers Sub-committee

• PDA Single Use Taskforce

• ISPE Disposables Community of Practice

Diagram by Jerry Martin Pall Life Sciences, Chairman BPSA

Typical Cell Culture Manufacturing Schematic

First Stage Disposables Implementation

Second Stage Disposables Implementation

Available Available –– Good ApplicationGood ApplicationAvailable. but must confirm process suitabilityAvailable. but must confirm process suitabilityAvailable Available –– Good ApplicationGood ApplicationAvailable. but must confirm process suitabilityAvailable. but must confirm process suitability

Available. but must confirm process suitabilityAvailable. but must confirm process suitabilityUnavailable at larger scalesUnavailable at larger scales

Liquid Storage and Mixing Systems

Bioreactors, Harvest & Downstream

Scale of Operations

10L

100L

1,000L

10,000L

10Kg 100Kg 1,000Kg

25,000L

100,000L

3,000Kg

2,000L

Fully Dedicated Facilites(500Kg to 3,000Kg)

Concurrent Multi-Product Facilites (10Kg to 1000Kg)

Clinical Production Facilites(2Kg to 30Kg)

Stainless Steel Envelope

Disposables Envelope

Source: Based upon initial concept by Jagschies, GE Healthcare, Bioprocess International 2007

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)

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

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

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?

Tubing & Connection Types

• Tubing types• Animal derived Component

Free (ADCF)• Tubing materials

• Platinum Cured Silicon• CFLEX• PVC• Ethyl Vinyl Acetate (EVA)

• Types of connection• Stainless Steel to Tubing• Tubing to Tubing

• Connectors• Aseptic connectors• Non Aseptic connectors• Tube welders & fusers

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

Space Requirement for Single UseReduced cleanroom floor space allocation

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

Typical Large Scale Cell Culture FacilityPotential Impact on Overall Site Utilities

2 x 15,000L bioreactorsIncl. USP + DSP

1 x 1,000L Pilot PlantLabs, Admin, CUBSite Infrastructure

POWER4.2 MVA

WATER720 M3/DAY

GAS1,010 NM3/HR

WASTE WATER631 M3/DAY

SOLID WASTE<200 TONNE/YR

12 x 2,000L disposable bioreactorsIncl. USP + DSP

1 x 1,000L Pilot PlantLabs, Admin, CUBSite Infrastructure

POWER1.9 MVA

WATER64 M3/DAY

GAS160 NM3/HR

WASTE WATER54 M3/DAY

SOLID WASTE<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

Transfer between rooms

ChromatographySkid

BUFFER HOLD PURIFICATION ROOM

ELEVATION

Buffer Hold Room

Purification Room

PLAN VIEW

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

Building Stacking Concepts - Horizontal

HVAC

Utilities Media Preparation & Cell Culture & Support Purif ication & Buffer Preparation & WarehouseMedia Hold Harvest Bulk Fill Buffer Hold

Horizontal Production Concept 1

HVAC

Media Preparation & Cell Culture & Support Purif ication & Buffer Preparation &Media Hold Harvest Bulk Fill Buffer HoldUtilities Support Utilities Warehouse

Horizontal Production Concept 2Both allow ease of material & personnel access to all production rooms without the use of stairs or elevatorsAvoids the transfer of tubing between floorsSuitable for Single Use (Disposables) and small scale stainless steel facilities

Building Stacking Concepts - VerticalHVAC

Media Preparation & Support Buffer Preparation &Media Hold Buffer Hold

Utilities Cell Culture & Support Purification & WarehouseHarvest Bulk Fill

Vertical Production Concept 1HVAC

Media Preparation & Support Buffer Preparation &Media Hold Buffer HoldCell Culture & Support Purification &Harvest Bulk FillUtilities Support Warehouse

Vertical Production Concept 2HVAC

Media Preparation & Support Buffer Preparation &Media Hold Buffer HoldCell Culture Support Purification

Harvest Support Purification &Bulk Fill

Utilities Support Warehouse

Vertical Production Concept 3Not for disposables, More suited to large scale stainless steel vessels

Production all at one level

Thanks to Elan Pharmaceuticals for kind permission to use this image created by PM Group

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

Lean manufacturingImportant 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

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)

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

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)

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

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

Impact on the project capital cost of disposables

• Cost impacts in our experience on conventional versus disposablefacility 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

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)

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

Summary of Disposables Pro’s & Con’s

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

Technical- Product Changover Time- Flexibility to change- Campaign Turnaround Times- Water Usage / Waste Water- Solid Waste Disposal- Leechable/Extractable Validation- Facility Size- CIP- SIP- Sustainability design

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

SlowerHighLess MoreSmallLarger

FasterEasy

FasterLow

HighSmaller

SlowerPainful

Traditional Stainless Steel Technology Disposables Technology

Complex SimplerComplex Simpler

Low High

Thanks – Any questions?

Contact details:

Andy RaynerGroup Director of TechnologyPM GroupKillakee House,Belgard Square,TallaghtDublin 24,Ireland

Tel: +353-1-4040700Cellphone: +353-87-2858296E-Mail: andy.rayner@pmg.ie