implementation of several new freeze dryers from ... · pdf fileimplementation of several new...

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


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


Steps and timeline7

Basic Design

DetailedDesign Construction

Qualification • FAT• SAT• IQ/OQ

Validation & Licensing•PQ / MFT•PV

Industrialization &

Production

Currently


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


What is a successful project?

SVP filling lines - Conceptual designFreeze dried products

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


Filling line10

Capper

Isolator


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


Freeze dryer13


Cooling system designCentralized cooling system

Compressors

LN2GN2

14

LYO 5 LYO 4 LYO 3 LYO 2 LYO 1

Loop Distribution

LYO 6


Cooling system15


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


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



18




– Qualification strategy– Cycle development & optimization


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


Industrialization & Production

OPTIMA SITES OCTAPHARMA SITESWHERE

D.Sierakowski

Basic Design DetailedDesign Construction

Qualification • FAT/SAT• IQ/OQ


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?

…………………………….


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!


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


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


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


FD Product� Expected specifications

Octapharma project

Content



29




– Qualification and Validation strategy– Cycle development & optimization


Qualification and Validation strategyScope

Validadion strategy => VMP

Risk based approach

30

Qualification strategy FAT/SAT – IQ/OQ

Qualification documentation


ValidationScope

6 freeze dryers with FLUS

4 different vials with 2 stopper sizes

31

4 different products

11 different strenght presentation


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


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


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


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


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


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


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


Freeze dried products• « like » water• are « water-soluble »

CIP cycle optimization41


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 €


Example withExample withFreeze drying cycle optimization

43

Freeze drying product T° mappingTo identify cold and hot product T° during FD cycles

Page 44


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


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


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]

implementation of several new freeze dryers from ... · pdf fileimplementation of several new...

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