CPPT 9010: Facility Design & Operation
D.I.T. DT275
Masters in Chemical and
Pharmaceutical Process Technology
26th November 2009
Clement Farrar
BA BAI MSc MIEI
1
Lecture Overview
1) Conceptual design
 2) Site Master Plan
 3) Tech Transfer
 4) Assignment Workshop

2
Conceptual Design
What is Conceptual design?



3
Result of many hours brainstorming, discussion…..
Formal and structured document
Fact not fiction
Conceptual Design
Definition/ Purpose






4
First and real quantified attempt to size, shape, program
and cost an investment
Provides a robust basis for investment decisions
Key element in feasibility study
Assists in facility location decisions
Basis for assessing local infrastructure
Basis for detailed design
Conceptual Design
Approach






5
The process is key - start with the process and provide optimal
conditions
Develop batch philosophy, sizing, frequency and throughput for
all stages
Size process elements and define space and servicing
requirements
Design outwards from process elements to other disciplines e.g.
utilities, HVAC, E&I, Civil/ Structural/ Architectural
Manage a coordinated design approach across all disciplines
Collect/ collate disciplinary input for cost estimation
Conceptual Design
Manufacturing Logistics





6
Essential as a good basis for concept
Full scale study begins with dose form and market projection
based on annual patient dose and patient population
Move backwards through doses, packs, lyo load, fill rate,
formulation batch size, vessel size and number, innoculum,
seeding etc to sees what’s required to meet the target (always
allow a safety factor)
Allow for qualification, cleaning, downtime, decontamination,
shifts, maintenance etc. in study
Move outwards from core process through CIP, Process Utilities,
General Utilities etc
Conceptual Design
Deliverables from Conceptual Design












7
Process descriptions and PFD’s (Process flow Diagrams) (not P&ID’s)
Equipment Lists, schedules and outline specs
Layouts and sections with classifications
Material and personnel flow studies
cGMP review
HVAC schematic and philosophy
Schematic for clean and general utilities
Electrical load calculations and SLD
Controls philosophy
Cost estimate +/- 25% (typical)
Project Schedule
Site Plan
Conceptual Design
Optional Deliverables






8
Planning Package
Selected Equipment
Specifications
Long Delivery PO’s
Negotiations with utilities
providers
Validation Master Plan
Validation input on long delivery
items
Conceptual Design
Develop Process





Remember the core purpose of the facility is to accommodate a
process or processes
‘Process’ can be fermentation, DSP, formulation, fill finish or even
packaging
A robust process with known output requirements is a basic
prerequisite
PFD’s are first Engineering Description of Process
Good PFD’s will show:





9
Equipment with sizes/ duties
Flows
Material Balances
Sequence/ Timings/ Durations
Cleaning/ Process Utilities needs
Conceptual Design
Equipment






10
Process equipment list is a critical document – for
planning, layout, costing etc
Key equipment sized from manufacturing logistics and
batch sizing (what is it required to do?)
Early vendor input is beneficial
Size and shape of equipment needed for concept stage
Configuration of process areas is based on equipment
sizing and access requirements
Decisions on ‘state of the art’ technology or older proven
technology
Conceptual Design
Critical Utilities





11
Start with process utilities and direct impact systems
Includes RO, WFI & Clean Steam
Can also include CIP (may be part of process)
Size and shape of generation plant, storage and
distribution
Other than CIP, which is integrated, most critical utilities
need to be close/ adjacent
Conceptual Design
HVAC & Classification




12
Critical in most areas of typical aseptic facility - more so
in fill finish
Have the classification discussions/ decisions early
In essence, HVAC plant and distribution need to be
adjoining to area served
HVAC, classifications are major determinant of ultimate
layout and indeed of most utilities
Conceptual Design
Layers






13
Apply layering concept
Layers roughly correspond to classifications
‘Core’ is where critical process takes place
In multi process facilities, there may be multiple cores
Adjacent layers – reduced need for proximity
Remote layers – not proximity dependent
Conceptual Design
Preliminary Layouts








14
Developed on ‘core outward’ basis
Classifications are critical - classification drawings
needed
Protection of process core areas – airlocks and garbing
Define pre and post inactivation
Separate entry and exit may be needed
Return corridors
Decontamination areas
Corridors critical – these can dictate classifications
Conceptual Design
Process Layouts






Sensible spacing
Common sense flow patterns
Ordered configuration
Access for Materials, Personnel, Maintenance
Engineering Aesthetics
Flow Priorities are:




15
Materials
Personnel
Fluids
Cable systems
Conceptual Design
Buffer Make-up





16
Biggest material movements in bulk
processing
Should be adjacent to formulation
Generally larger overall volumes than core
process
May require material handling, dust control
etc
Sterile filtered at this point
Conceptual Design
Clean Utilities & CIP





17
CIP/ SIP are integral parts of a process design
WFI generation, storage and loop distribution
Clean Steam generation & distribution
Significant space required
CIP circuits should be as short as possible/ integrated –
design for gravity return where possible
Conceptual Design
Access & Communications Corridors






18
Keep material movements under cover
Link corridor preferred – also favour straight spine with
buildings either side
Warehouse is focal here – more so for fill/ finish than
bulk
Personnel facilities are important – significant time
losses in canteen or rest room trips (smoking areas?)
Also truck access to be addressed
Link corridor may be at 2 levels
Conceptual Design
Warehouse/ Material Movements





19
Calculate number of pallets - no shortcuts here as
operations are specific
Minimum level for large plant is narrow aisle with 7-8
pallets high - requires 0.5 m2 per pallet
Traditional low profile needs 2.0m2 per pallet
Decisions on receiving/ dispatch, sampling, dispensing
etc
Warehouse configuration drives site layout
Conceptual Design
Personnel Movements





20
Essential personnel only close to process (balance
garbing and accommodation costs against proximity)
Secondary/ tertiary garbing must be close
Normal now to have separate in/ out flow passages
Separate primary change/ lockers/ toilets/ showers
Analyse movements – may justify multiple cafeterias,
toilets, primary change areas
Conceptual Design
Decisions on Height






21
Fill/ Finish height – usually single process floor
Bio facility ideally at least 3 floors: Process is
sandwiched between HVAC and CIP (utilities)
Process utilities can be above, below or alongside
Two floor process drives us to 4 floor ideal (e.g. 12500L
Vessel)
Warehouse height – min 12m
Admin & other heights based on footprint available
Conceptual Design
Air Handling








22
Layouts and classification drive HVAC sizing
HVAC plant is a big space user – plant room footprint usually
exceeds total process area (top floor)
Early decisions needed for walk-on concept, interstitial spaces
etc
Care with intakes and exhausts – allow segregation
Decision re: LPHW or steam as heating medium
Don’t over specify humidity limits – costly
Smart recirculation policy based on energy efficiency
Separate once-through needed for ‘active’ spaces
Conceptual Design
Utilities – General






23
Biggest user is HVAC – next is Process Utilities
Assess demands for these users
Size primary generation equipment – use modular
approach >3 units
CUB (Central Utilities Building) concept now fairly
universal
CUB usually remote to avoid interference with
expansion plans
Smart planning for pipe racks and distribution
Conceptual Design
Electrical







24
Size from load list and utilities requirement
Apply diversity factors based on experience
Locate MCC’s adjacent to loads
Decision on standby generation and scope
Assess local reliability and capacity
Policy on centralized versus distributed
transformers
Consider renewable/ sustainable energy
Conceptual Design
Controls & Automation





25
Early decisions on general principles:
PLC vs. DCS
Similarly for scope of communication
and networking
Avoid ‘nice to have’ items – can result in
downstream complications
Similarly avoid ‘state of the art’ – usually
untested and may result in unknown
complications
Remember need for aseptic interfaces
Conceptual Design
Finishes






26
Policy decision re: proprietary partition vs. traditional
stud
Similar decisions for floors, ceilings, doors and windows
Again, remember Baselines Guides for economical
solutions
Proprietary partitions cost significantly more – don’t be
fooled
They can however save significantly in time, use of wet
trades, disruption
They also look better (makes facility more impressive)
Clean Room Wall Make-Up
STICK BUILT
 Cold formed Metal stud
frame system.
 Gypsum plaster board
Plaster skim coat.
Spray applied
STERIDEX paint system.
Wall protection.
MODULAR
 High pressure
laminate. (Or steel panel)
.
27
Advantages:
 Theoretically more economical.
Disadvantages:
 Coordination of trades.
 Wet & dusty construction.
 Schedule impact
Advantages:
 Pre fabricated.
 Quality control
 Parallel work faces - Schedule
advantage
Disadvantages:
 More expensive (Depending on system)
 Integral wall protection.
 Demountable.
Conceptual Design
Structure/ Civil






28
Design develops from layouts, height
decisions, size, shape etc
Site structural capability needs to be
assessed
Special requirements for super flat floors
in warehouses etc
Integrate drainage requirements – all
types
Site development, roads, car parks,
landscaping
Remember special requirements e.g. Fire
Protection, Earthquake etc
Conceptual Design
Cost Estimate





29
Amount of effort depends on accuracy required
Process Equipment costs usually based on mix of vendor
enquiries and engineers database
Process utilities normally costed on similar basis
Process piping based on estimated run length and
composite unit costs can be factored
HVAC can be based on actual sizing costs for core areas
and factored per square meter or cubic meter for others
Conceptual Design
Cost Estimate (cont.)






30
Utilities costed on actual sizing and database costings
Distribution costed on estimated length and composite
costs, or can be factored
Electrical costs based on points at various load sizes –
derived from loads list
Field Instruments based on count and category – add a
premium for aseptic quality
Automation costed based on I/O count
Extra added for special cGMP requirements e.g. GAMP
and Part 11
Conceptual Design
Cost Estimate (cont.)
 Include for:
 Professional
design – Basic &
Detailed
 Validation – C&Q
 Construction Management
 Permitting
 Client Internal Costs
 Contingency
31
Conceptual Design
Schedule
Critical aspect – must minimise time
to market
 Be realistic even though it’s years away!
 Allow for decisions, approvals,
 objections, contingencies
 Allow for disruption and include constructability study
 Beware of false assumptions on feasibility of existing
site
 Consult all parties early on and get agreement on big
decisions

32
Conceptual Design
Summary




33
Apply serious front end loading at concept stage
A poorly assembled concept can be a ‘milestone’ for
later stages
Remember even the best estimates will omit some items
– allow for unforeseen
On the other hand – don't kill it by being too
conservative
Formulation & Vial Fill/ Finish Process
10
CONJ.
FORMULATION ROOM
BUFFER
PREP
FORMULATION
VESSEL
MOBILE
TRANSFER
VESSEL
MOBILE
TRANSFER
VESSEL
Transfer Room
MANIFOLD
F
F
WASHER
VIALS
REGIONAL
PACKAGING
DEPYRO
VIAL
TUNNEL
FILLER
VIAL
STOPPER
WAREHOUSE
SEMI AUTO
VISION SYS
COLD
MANUAL
TRAY
STORE
PALLETIZER
LOADER
AUTOVISION
SYSTEM
TRAYS
34
CAPPER
Formulation and Syringe Fill/ Finish
Typical Output
Grade C
Formulation
200,000 Syringes
Buffer Make-Up
Vessel
Filter
Buffer
Hold Vessel
Filter
Conjugate
Download
Conjugate
Pooling Vessel
Filter
0.22 μm
Filters
Product
Vessel
AlPO4
Can Upload
Filling & Inspection
1 day
Grade C E-Beam
Product
Vessel
Grade A Room/ Isolator
Surge
Tub
Filling
Vessel
Sterilisation Recirculation
Stoppering
2 days
35
Grade D
Automated
Inspection
Product
Ready
Syringe Filling & Inspection
36
Syringe Filling Process
37
Syringe Filling Line Layout
Elevation View
INFEED
ISOLATOR
OUTFEED
Plan View
38
E-Beam Process Plan



GRADE C
INFEED
GRADE C
SUPPLIED
E-BEAM
TUNNEL
PRE+44Pa
IRRADIATION
GRADE A
SUPPLIED
E-BEAM
TUNNEL
POST+74Pa
IRRADIATION
+54Pa
E-BEAM
EXHAUST
AIR FLOW
MATERIAL FLOW



POINT OF SURFACE
DECONTAMINATION
Plan View
39
Isolator and Outfeed Process Plan





GRADE A
DELID /
DELINER
GRADE A
NESTED UDF
FILL /
STOPPERING
GRADE A
OUTFEED
BUFFER
GRADE C
MOUSEHOLE
UDF
HIGH FLOW
GRADE C
BACKGROUND
+84 Pa
+84 Pa
+84 Pa
+54 Pa
+54 Pa
MATERIAL FLOW
AIR FLOW
WASTE FLOW





Plan View
40
Vial Fill Finish Layout
41