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Implementation of several new freeze dryers
From conceptual design toFreeze Drying Technology Transfer
OctapharmaDominique Sierakowski
Head of Corporate Pharmaceutical [email protected]
Octapharma company snapshot
– Plasma products manufacturing
– Company founded in 1983
– About 4000 employees
– Sales in > 80 countries
– R&D focus on human proteins for human therapy
Mission statementFor the safe and optimal use of human proteins
Manufacturing activities
– Parenteral vials liquid and freeze-dried products– Immunology - haematology - intensive care
– Manufacturing facilities in 5 countries
– Current major investments in the aseptic processing area:
– Filling lines– Freeze dryers
User requirementsA freeze drying plant
Without
– Product loss– Breakdowns– Deviations
4
– Deviations
With the right level of performance
Highly flexible
– Easy to validate– Easy to use– Easy to maintain
Evolutive
Not expensive
30/09/2013 D.Sierakowski
Octapharma projectPresentation
Contents
Project presentation and goals
Freeze dryers design and layout
5
Project management items
Needs and Specifications - URS
Steps from conceptual design to Freeze Drying Technonolgy Transfer
– Validation strategy– Cycle development & optimization
30/09/2013 D.Sierakowski
Octapharma projectImplementation of new equipment in 4 different site s
Current SVP & Freeze dryers project
– SVP filling lines (Small Volume Parenteral filling lines)– 6 Freeze Dryers (FDs) – Automatic Loading and Unloading Systems (FLUS)
6
PHARMA FORUM
– Automatic Loading and Unloading Systems (FLUS)
Basic Design
DetailedDesign
Construction FAT
Qualification • SAT• IQ/OQ
Validation & Licensing• PQ• MFT• PV
Production
2010 2012 20132011 2014
30/09/2013 D.Sierakowski
Steps and timeline7
Basic Design
DetailedDesign Construction
Qualification • FAT• SAT• IQ/OQ
Validation & Licensing•PQ / MFT•PV
Industrialization &
Production
Currently
30/09/2013 D.Sierakowski
ProjectsQ1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4
SVP & FLUS6 FD
Order PQ & MFTDelivery time - FAT Ready for product validation startingAssembly - SAT/IQ/OQ
2010 2011 2012 2013 2014
Octapharma projectSix freeze dryers
All decisions were (are ) very hard with always strong impacts on
– Budget– Timeschedule– Final results in terms of Quality and Production outputs
8
Cost
Time schedule
Quality
– Final results in terms of Quality and Production outputs
Risks are big
– first for the customer (final user)– but also for the supplier
30/09/2013 D.Sierakowski
What is a successful project?
SVP filling lines - Conceptual designFreeze dried products
Page 9
WASHINGSTERILIZING
TUNNELFILLING STOPPERING LOADING
FREEZE
DRYING
CAPPINGCODINGTRAYING UNLOADING
– Vials 6 to 100 ml (tubing and molded glass)– Stoppers 20 & 32 mm – “Lyoseal” 20 mm
– Batch size 2000 to 20 000 vials– Filling volume 1 to 50 ml
30/09/2013 D.Sierakowski
Filling line10
Capper
Isolator
30/09/2013 D.Sierakowski
Washer
Tunnel
Filler TransferIsolatorAirlock
FreezeDryers
11
CapperIsolator
Filler
Stopperingstations
D.Sierakowski30/09/2013
Freeze dryer design
Monobloc design :
– one chamber with a separative valve between drying chamber and condensor
2 pizza doors
1 main door (full opening)
12
About 10 m²
Stoppering hydraulic system
CIP/SIP/WIT
D.Sierakowski30/09/2013
Freeze dryer13
30/09/2013 D.Sierakowski
Cooling system designCentralized cooling system
Compressors
LN2GN2
14
LYO 5 LYO 4 LYO 3 LYO 2 LYO 1
Loop Distribution
LYO 6
30/09/2013 D.Sierakowski
Cooling system15
30/09/2013 D.Sierakowski
FLUS design16
ALC (Automatic
loading cart)
ALT (Automatic loading table)
Rail system
Filler VFVM 7031
Capper VVM 7012
Rail system
FD 1FD 2FD 3FD 4FD 5FD 6
AUT (Automatic unloading table)
AUC (Automatic unloading cart)
Slot door
Slot door
Guiding rail with power supply
Guiding rail
UPS
UPS
Infeed transport belt
Discharge transport belt
Vial coding
EVK 7000
Guiding rail with power supply
30/09/2013 D.Sierakowski
Washer VWM 218
Tunnel SHT9L-IR-SKZFlexible loading/unloading system without frames
– Pass through layout– Loading vials shelf by shelf– Loading side with a formatting table and a mobile cart and active RABS – Unloading side with a mobile cart and a deformatting table and active
RABS
Octapharma project
Content
Project presentation and goals
Freeze dryers design and layout
18
Project management items
Needs and Specifications - URS
Steps from conceptual design to Freeze Drying Technonolgy Transfer
– Qualification strategy– Cycle development & optimization
30/09/2013 D.Sierakowski
Overall Project Manager
Octapharma
Project SponsorProject Sponsor
OverallProject Manager
Optima
Project SponsorProject Sponsor
Filling line IsolatorFreeze Dryer Filling line IsolatorFreeze Dryer TEAM
Documentationplateform
Project managementA mirror organization
TEAM
Documentation
Qualification
M&PM&PInnova KleeKlee Project Leaders
AUSTRIA SWEDEN GERMANYFRANCE
Documentation
Qualification
Project Leaders
Project managementResponsabilities
Page 20
OPTIMA + OCTAPHARMA OCTAPHARMARESPONSIBILITIES
SUPPLIERSChange Control management
ECR
OCTAPHARMAChange Control management
CC SOP
30/09/2013
Basic Design DetailedDesign Construction
Qualification • FAT/SAT• IQ/OQ
Validation & Licensing•PQ / MFT•PV
Industrialization & Production
OPTIMA SITES OCTAPHARMA SITESWHERE
D.Sierakowski
Basic Design DetailedDesign Construction
Qualification • FAT/SAT• IQ/OQ
Validation & Licensing•PQ / MFT•PV
Industrialization & Production
Project managementHarmonisation
Page 21
H A R M O N I Z A T I O N
OPTIMA + OCTAPHARMA OCTAPHARMA
30/09/2013
HARMONIZED EQUIPMENT
HARMONIZED DOCUMENTATION
H A R M O N I Z A T I O N
Validation
Production
Maintenance
Protocols
Reports
SOPs
HARMONIZED PROCESSES & METHODS
Training modules
Master Batch Report
D.Sierakowski
End of design phase
22
End of design phase
Experiences
D.Sierakowski
First difficultyWhat are the needs: some examples
MKS gauges => 1 or 2 or 3 or .. 4?
Vacuum pumps => dry pumps or oil seal pumps?
Compressors or LN2 => ?
23
Cost
Time schedule
Quality
A must?A Necessity?A wish - « Nice to have »?
Compressors or LN2 => ?
Redundancy strategy
– Cooling system => yes or no?– PLC and SCADA => yes or no? Level?Separative valve => yes or no? => dimension?
Mass spectrometer => yes or no?
Automatic loading and unloading => yes or no?
…………………………….
D.Sierakowski30/09/2013
Second difficulty: decisions managementHow to make the decisions
Who takes the decisions
What is the difference between a decision and a final decision?
How to be sure that the final decision is the right decision?
How to deal with:
24
How to deal with:
– « to make sure »– « in case of »– « we are doing like that for ... »– And inspectors « speculative future potential requirements »
Decisions must be based on figures and rationals
not based on opinions!
D.Sierakowski30/09/2013
Preparation cycles Freeze drying cycle
Sterilization in place
Filter integrity test
Cleaning in place
FILLING
The processesWhat are the needs?
25
Filter integrity test
De icing
Freeze dryer leak test
Stoppering
Freeze drying
Capping
Loading
Unloading
30/09/2013 D.Sierakowski
The freeze-drying process is complexWhat are the needs?
Page 26
Product & packaging�Batch size�Number of units -50
-40
-30
-20
-10
0
10
20
30
40
0
200
400
600
800
1000
1200
Congélation MSV Dessiccation primaire Dessiccation secondaire
Chargement Bouchage
Déchargement
NEEDS
30/09/2013 D.Sierakowski
Freeze dryer�Design�Performance
Building�Freeze dryers size�Freeze dryers design
LIMITATIONSOthers�Budget�Timeline
The freeze-drying process is complexFD design and Processes will have a direct impact on qualityattributes of the products
Page 27
Processes� Preparation cycles� Freeze-drying cycle
-50
-40
-30
-20
-10
0
10
20
30
40
0
200
400
600
800
1000
1200
Congélation MSV Dessiccation primaire Dessiccation secondaire
Chargement Bouchage
Déchargement
Freeze dryer� Design� Performance
30/09/2013 D.Sierakowski
FD Product� Expected specifications
Octapharma project
Content
Project presentation and goals
Freeze dryers design and layout
29
Project management items
Needs and Specifications - URS
Steps from conceptual design to Freeze Drying Technonolgy Transfer
– Qualification and Validation strategy– Cycle development & optimization
30/09/2013 D.Sierakowski
Qualification and Validation strategyScope
Validadion strategy => VMP
Risk based approach
30
Qualification strategy FAT/SAT – IQ/OQ
Qualification documentation
30/09/2013 D.Sierakowski
ValidationScope
6 freeze dryers with FLUS
4 different vials with 2 stopper sizes
31
4 different products
11 different strenght presentation
30/09/2013 D.Sierakowski
Risk analysis approach33
NAME OBJECTIVE TIMELINEMETHOD
FROM
Design Risk Analysis
To ensure an adequate design to eliminate avoidable risks for quality, productivity and safety
prior to construction
FMECA
Component Criticality Analysis
To optimize the effort by focusing on "Product quality impact" components
prior to FAT/IQ/OQ
ISPE
30/09/2013 D.Sierakowski
Process Parameters Analysis
To define CPPs and acceptance criteria for PQ prior toSAT/PQ
internal method
ContaminationRisk Analysis
To decrease or eliminate avoidable risks of contaminationTo define Environmental Monitoring ProgramTo draft aseptic activities SOPs.To prepare MFT protocols
prior to MFT
internal method (based on HACCP and FMECA)
Product Mapping
Define, for Process Validation, acceptance criteria for Critical Quality Attributes and Critical Process Parameters (for CPP = upper and lower limits)
prior to PV
internal method
Preparation cycles testsCIP/SIP/WIT/LRT
34
Freeze dryers FAT SAT OQCycle
devel t PQ Purpose Parameters Comments
Preparation cycles => Cleaning / Sterilisation / Fi lter Integrity Test / Leak Rate Test (CIP/SIP/WIT/L RT)
CIP coverage X XReferSAT
X
To verify that the complete internal surfaces of chamber, condenser as well as internal parts and components (e.g. shelves, tubing, hoses etc.) can by sprayed/reached and thus cleaned by the CIP spraying balls and nozzles.
The complete internal surfaces are visually inspected for residues
FAT / SAT / OQ =>Test solutionRiboflavin orSodium hydrogen carbonate
One test need to be done during commissionning on dryer to check the efficency of the last optimized CIP cycle
SIP - Temperature distribution study
X XReferSAT
X
To verify uniform distribution of saturated steam by using temperature measurement.
To identify the cold spots and hot spots within the chamber, the condenser, filter, pipings and in the drains during sterilisation.
• Variation in the temperature measured by each probe• Variation in the temperature measured from probe to probe• Difference in temperature between the probes and the set temperature of FD (drains T° probes)
Number and positioning of sensors explained in a rational
Measurements sensors will be placed both in contact with internal (eg. 24 probes) surfaces and in the ambiance with same position as certain contact ones (eg. 6 to 8 probes)
SIP performance (drying / cooling)
X XReferSAT
XTo verify the drying and the cooling of all internal surfaces after SIP cycle / before ready for loading
1. T° measurement sensors should be placed on internal surfaces which are identified as difficult to cool down => eg.: main door
2. All internal surfaces visually dry specially condensor piping
Data analysis:- Variation in the temperature measured by each probe
CIP - Coverage test SIP - Sterilisation mapping WIT - Filter integrity test LRT - Leak Rate Test
30/09/2013 D.Sierakowski
SIP - Temperature penetration study (with BIs)
XXX
To verify uniform distribution of saturated steam by using temperature measurement
To verify the efficiency of sterilization process by using biological indicators.
- Variation in the temperature measured by each probe- Variation in the temperature measured from probe to probe
- Difference in temperature between the validation probes and the set of process probes (FD drains T° probes)
-Temperature/pressure couple in conformity following Regnault table (∆P between measured pressures and calculated values for saturated steam ≤ 50 mbar)
- No critical alarms recorded and cycle in conformity following SOP
Biological indicators negative (inactivation of 6 log)
Measurements sensors should be in contact with internal surfaces
Biological indicators are used and are placed at positions where it has been determined during thermal mapping that sterilizing conditions are most difficult to achieve (cold spots).
Number and positioning of sensors and BIs' explained in a rational
WITFD_FT X X
ReferSAT
XXX
To verify:- WIT parameters and acceptance criteria compare to supplier validation guide (Sartorius)- Drying of the filter after SIP and WIT cycles
Filter supplier acceptance criteriaDrying - filter cartridge weight before and after cycles
Leak Rate Test X XReferSAT
X
To verify that all parts of freeze dryer exposed to the "product" need to be included in the test.
The machine does not exceed a defined leakage rate (Q[mbar*l/s])
The machine must be clean and dry
Leak rate calculationPressure Rise Difference (mbar) X System Volume (Litres) / Time (Seconds)
Test parameters
1. Preparation step (drying and stabilization)
2. Test- leak pressure: 10 µbar- leak test time: 60 min (t)- leak rate: mbar*l/s
Qualification
≤ 2 x 10-2 mBar-L/ sec.
Routine production - Acc. crtiteria must be defined based on trending for a specific FD and according to test conditions (residual moisture, stable T°,..) - linked to LRT
Re-Qualification test2 times per year before MFTBefore / after maintenance (depending on actions)
Overall preparation cycle X X
To verify total time from end of unloading to ready for loading with required loading temperature (de-icing - CIP - SIP - WIT - LRT)
To verify the linking of each cycle
Time from door closing after unloading to door opennig for loading
LRT - Leak Rate Test
Preparation cycles time (CIP/SIP/WIT/LRT)
Freeze drying tests35
Freeze drying cyclesVacuum system
Vacuum performance X XReferSAT
To verify that the vacuum system is in compliance with the defined requirements: vacuum pump down rate
The rate is pressure function of time
This rate is the measure of time that is required for the pumping system to reach a specific pressure level. Included in this test is the lowest pressure obtainable for the system.
Vacuum controlCan be combined with "vacuum performance"
X XReferSAT
To verify, that the automated vacuum control is in compliance within the defined range and defined tolerances.
Pressure - according to tested set points: Xµbar
Shelf system - heat fluid transfer system
Cooling performance - empty chamber
X XTo verify that the shelf cooling rate of the machine is in compliance with the requirements for temperatures and time under atmospheric conditions and empty
- cooling capacity empty
Cooling performance - "bulk" full loadcan be combined with max FD load
X XReferSAT
To verify that the shelf cooling rate and temperature control of the machine is in compliance with the requirements for temperatures and time under atmospheric conditions and with load of product (X Kg water)
- T° regulation (Shelf Temperature Set Point Control)- cooling capacity
Shelf heating performance - "bulk" full load
X XReferSAT
To verify that the shelf heating rate and temperature control of the machine is in compliance with the requirements for temperatures and time under atmospheric conditions and with load of product (X Kg water)
- T° regulation (Shelf Temperature Set Point Control)- heating capacity
Shelves mapping study(empty = unloaded)
X XReferSAT
To verify that during freeze-drying the temperature distribution on the shelves in unloaded condition complies with the specified acceptance criteria
1. Pre calibration (before the measurement)
2. Measurement of T° distribution:T°mapping According to FD recipes - eg.• +30°C• 0°C• -40°C• -55°C• minimum T°C (for info only on one FD)• maximum T°C (for info only on one FD)
- 5 sensors per shelves positioned at each corner and in the middle of the shelf.- 2 sensors to measure T° of the shelves package inlet and outlet (can be outside the chamber)
Lowest and highest shelf temperature must be evaluated during SAT (only For Info)
Shelf Temperature Performance (heating and cooling) Condenser cooling and CapacityShelf Temperature mappingSublimation TestStoppering test
30/09/2013 D.Sierakowski
outlet (can be outside the chamber)- Shelves measurements with "Contact device"
3. Post calibration of sensors
Freeze drying capacity
Sublimation rate X XReferSAT
To verify, that the sublimation rate is in compliance with the defined specifications with worst case production recipe
Differential pressure between drying chamber and condensor chamber
Amount of water transfer from chamber to condensor > X kg/h
Stoppering systemthen confirmed by FD cycles below
X XReferSAT
Tto verify that the stoppering system works correctly with all formats
The vials are closed under vacuum conditions with stoppers.The stoppering mechanism should be tested to ensuresmooth operation, eg there should be no jerky movements and the system should stopper according to recipe and correct specification
FD cycle maximum filled vials load
X
1. To verify that the freeze-drying program complies with the set programme parameters (recipe) maximum load
2. To verify the ability of the system to perform the process following specific batch recipe
- maximum load & filled units
- critical process parameters => CCPs=> Pressure, shelf T° and time
- operational process parameters => OPPs=>condensor T°, differential shelf T° infeed/outfeed, differential pressure between chamber and condensor
- stopper postion (insertion)
Maximum load = all the shelves loaded with maximum number of filled vials per shelves.TBD = volume per vials
FD cycle minimum filled vials load
X
1. To verify that the freeze-drying program complies with the set programme parameters (recipe) maximum load
2. To verify the ability of the system to perform the process following specific batch recipe
- minimum load & filled units
See - FD cycle max load - vials load test
Condensor performancecombine with FD cycles above
X
To verify that the CCS has no impact on the refrigeration systems regulation and capacity (shelf T° and condensor T°) on each FD.To verify, that the CCS is running within the defined specifications with worst case production planning scenario concerning CCS
Shelf temperature controlCondensor T°
Condensor capacity
Condensor capacity XReferFAT
To verify, that the capacity (maximum ice quantity which can be deposited on the cooling coils of the condenser) is in compliance with the defined specifications
Ice capacity => amount of ice (X Kg)
Condensor de-icing combine with FD cycles above
XReferFAT
To verify that the defrosting At the end of the process no ice remains on the condenser.
Condensor chamber dry.
Stoppering test
Loading/Unloading performances (semi and automatic system)
Cycles developmentoptimizationWhen, What and Why?
After IQ/OQ before starting PQ
Make studies to
– Evaluate performances of the plant
36Cycles development
ISPE source
V Model
– Define (reachable) ranges for PQ– Gain confidence and develop knowledge of operators– Optimize the processes (preparation and freeze drying)– Prepare the freeze drying transfer
Time and cost demanding - But positive impacts
– Deviations - validation and routine production– Running costs
D.Sierakowski30/09/2013
FAT
Component CriticalityAnalysis
Design RiskAnalysis
Design Review Report
Freeze Dryer
Qualification Master Plan
QMP
Currently cycle optimization and studiesExamples
SAT
IQ
OQ
QUALIFIED SYSTEMS
PQ
Process ParameterAnalysis
CYCLES DEVELOPMENT
30/09/2013 D.Sierakowski
CIP cycle optimization
Freeze drying product T° mapping
Example withExample withCIP cycle optimization
38
CIP system design
No recirculating pump
Distribution manifolds with spray nozzles
in drying chamber and condenser
Automatic sequential process
The shelves are moving up and down
39
The shelves are moving up and down
during CIP cycle
Self draining design
Conductivity sensor at the drain
Hot T° WFI & steam & air compressed
D.Sierakowski30/09/2013
Freeze dryers and CIP systemWe must remember
The CIP system will be never able to take away fallen vials/stoppers or glass breakages
Qualification coverage test
The test method can impact cycle time and water consumption
40
This is the reason why CIP cycle development is interesting
D.Sierakowski30/09/2013
Freeze dried products• « like » water• are « water-soluble »
CIP cycle optimization41
30/09/2013 D.Sierakowski
CIP cycle developmentResults
FAT coverage test => Good results with Riboflavin test
– Cycle time => About 90 minutes – Water consumption => more than 4 M3
42
Cycle optimization
– Cycle time => About 50 minutes – Water consumption => less than 2 M3
Impact for the company with more than 400 CIP cycles per year
– WFI saving about 1000 M3 => Cost saving – depending on WFI cost - about 100 000 €
30/09/2013 D.Sierakowski
Example withExample withFreeze drying cycle optimization
43
Freeze drying product T° mappingTo identify cold and hot product T° during FD cycles
Page 44
30/09/2013 D.Sierakowski
Freeze drying cycle developmentResults
Good knowledge about the behavior of the product in the new FDs
Cold and hot product T° during each phase of freeze drying are identified
Acceptable ranges can be defined for the next qualification steps (PQ)
45
Acceptable ranges can be defined for the next qualification steps (PQ)
Robust information before starting freeze drying cycles transfer from our olddryers to the 6 new dryers
Robust rational to define the sampling plan for Product Validation
30/09/2013 D.Sierakowski
Next steps
Start Performance Qualification
Goal => to be able to PROVE that the 6 freeze dryers are identical
46
Stakes => reduce the effort for Product Validation
30/09/2013 D.Sierakowski
47
Thank you for your attention.
Any Questions?
Freeze dyers « life cycle »
D.Sierakowski
« ProjectLife cycle »
3 years
« ProductionLife cycle »
30 years
30/09/2013
OctapharmaDominique Sierakowski
Head of Corporate Pharmaceutical [email protected]