Fedegari Aseptic Technology Integration: Case Study. Sergio Mauri, Director, Global Integrated Projects

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1 Fedegari Aseptic Technology Integration: Case Study Sergio Mauri, Director, Global Integrated Projects

A family owned company 430 employees all

Fedegari Group is the holding company of

companies located in Italy, Switzerland,

Designing and manufacturing of equipment

2 A family owned company 430 employees all over the world 60 Million turnover Fedegari Group is the holding company of an international group composed of 7 companies located in Italy, Switzerland, Germany, Singapore, China and USA Designing and manufacturing of equipment for pharma, biotech and food industries. In-house manufacturing of all critical components Total control of technology and process.

3 Fedegari Group All over the world Fedegari Group companies

4 Fedegari uniqueness Total control of technology through internal design/manufacturing; Provider of complete solutions; Delivery of turn-key systems all factory tested; Unconventional approach in developing innovative solutions; Constantly seeking new technology challenges; Higher reliability thanks to the many field-tested subsystems/components.

5 Case study Multipurpose pharmaceutical forms production original layout CUSTOMER CONCEPT LAYOUT

6 Main Fedegari targets Process simplification and reliability increasing; Materials & People flows shorting and optimization; Cross-contamination risks reducing; Increasing in GMP reproducibility and compliance of washing, sterilization and decontaminations operations; Lower life cycle cost of equipment; Commissioning & Validation activities simplification.

7 Scope of the streamlining Flow patterns separation between materials, personnel, clean and dirty; Select new terminal sterilizer with 2 doors to avoid non sterilized/sterilized products; Reduce manual washing activity and space; Decontamination of materials passing in controlled area; Pass box for waste material from controlled area; Transfer of sterilized machine parts to reassembly & transfer of pre-stoppered vials to lyo with a class A continuity.

8 Layout design implementation Multipurpose pharmaceutical forms production new layout FLOW PATTERNS LAYOUT

9 Case study cont. Separation and reduction in material/people flow and layout design AREA CLASSIFICATION EU ANNEX 1

10 Washing and Sterilizing Process Single equipment integrating 3 processes : Decontamination Washing Sterilization The unit footprint is the same of the equivalent steam sterilizer autoclave.

11 Case study cont. Separation and Saving in material/people flow and layout design Washing, sterilization, drying, modified Lay-out with FOWS WASHING/STERILI ZING FLOW PATTERNS

12 Traditional layout configuration ASEPTIC CORE LEGEND FORMULATION STERILIZER WASHING DECONTAMINATION STERILIZATION CLEANED STORAGE WASHER VHP PASS-BOX CLEANED STORAGE VHP PASS-BOX STERILIZER WASHER ASEPTIC CORE WASHING AREA

13 FOWS layout configuration FORMULATION LEGEND WASHING DECONTAMINATION STERILIZATION CLEANED STORAGE FOWS ASEPTIC CORE CLEANED STORAGE FOWS ASEPTIC CORE WASHING AREA

material to be cleaned; Multipurpose machine: washing and

1controller No pressure vessel; Clean steam injected into

14 Washer Sterilizer or Steam Washer? Better Cleanroom space management; Reduced routing of material to be cleaned; Multipurpose machine: washing and sterilizing; Simpler qualification approach: 2 process- 1controller No pressure vessel; Clean steam injected into the chamber; Cleaning PW heated by steam, NO heaters; Sustainable and eco friendly process.

effectiveness; Shorter rinsing and lower WFI or PW water

15 The power of steam Emollient effect on the soils; Detergent reduction used in the cleaning process; Disinfection effectiveness; Shorter rinsing and lower WFI or PW water consumption; Less energy consumption and cost of ownership; Washing performance highly improved

Cleaning process Part to be cleaned 3D dwg, physical

analysis Detergent choice Efficacy against the soil

cycle development Rinsing time Part drying Temp.

16 Cleaning process Part to be cleaned 3D dwg, physical parts development Soil type Chemical and biological analysis Detergent choice Efficacy against the soil Cleaning process recipe According to Fedegari DB Washing cycle development Rinsing time Part drying Temp./Time Bespoke to customer process requirements Cleanliness check Conductivity/T OC

17 FOWS Typical applications Decontamination & Washing + Sterilization process: bin, hopper, filling equipment machine parts Decontamination means to remove contaminants from objects (by washing, chemical or thermal treatments) before any other process; The standard approach to decontamination washing and sterilization means three processes on three different equipment.

18 FOWS video

19 FOWS Conclusions Multipurpose equipment with autoclave and washing machine characteristics; Better washing performances compared to standard washing machines (steam, vacuum); Only one equipment to maintain and one user interface to know; Only one validation protocol for sterilizing and cleaning process; Reduced validation time for single execution of mutual tests of autoclaves and washing machine.

20 Case study cont. Air/Steam or Super Heated Water Spray Terminal Sterilization Terminal sterilization modified Lay-out with double door sterilizer TERMINAL STERILIZATION ROUTING

21 Terminal sterilization Terminal sterilizer designed to handle various types of pharmaceutical products. Two different approaches: Air/steam for PFS, LVPs and SVPs soft containers, at the end DRY LOAD; Water spray for LVPs and SVPs containers, at the end WET LOAD.

22 Superheated water autoclave

23 Air/Steam autoclave

24 Load handling examples

25 Case study cont. Separation and Saving in material/people flow and layout design Sterile material transfer and Class A continuity with HEPA Carts CLASS A CONTINUITY ROUTING

container transfer; To store overnight filled vials before freeze

26 FHC LAF mobile HEPA-Cart Sterile material transfer and storage within the aseptic suite; To maintain an ISO 5/CLASS A Continuity in primary container transfer; To store overnight filled vials before freeze drying; To maintain the sterility and to store unpacked tools sterilized and dried.

27 Case study cont. Separation and Saving in material/people flow and layout design Heat sensible material transfer IN &OUT and surface chemical bio-decontamination CHEMICAL SURFACE BIO- DECONTAMINATION

28 Vaporized H 2 O 2 decontamination unit The FCDV unit is designed to achieve surface bio decontamination of any items compatible with vaporized H 2 O 2. This kind technology has been implemented in order to reach a 6 log reduction of the bio burden.

29 Load pattern examples

30 Material transfer routing Steam Sterilization HPV Decontamination Aseptic Core Dry Heat Sterilization Spray & Pray E-Beam

31 Available technologies Nothing plus interlocked doors Spray & wipe & pray LAF and UV irradiation HPV transfer hatch Dry mist Chlorine Dioxide gas Nitrogen Dioxide gas 31

32 Risk assessment approach What are the risks involved in an uncontrolled material transfer process? Health damage by supplying a contaminated product; Batch product rejection; Product shortage; Increased production downtime; Inspection failure. These are the risks not having a good system

Surface bio-decontamination drivers Plastic

Aseptic Processing less cleaning and downtime;

sensitive items might magnify the risk of

33 Surface bio-decontamination drivers Plastic Single Use devices more and more used for Aseptic Processing less cleaning and downtime; Primary containers, stoppers, clean room garments etc. outsourcing; Material transfer of heat sensitive items might magnify the risk of viable contamination delivery into the sterile suite; HPV surface bio-decontamination can mitigate this risk.

34 Risk in aseptic processing Product/ Material IN/OUT Suite Design, RABS/Isolator Equipment Design Qualification, Validation Sterilization Environment Cleaning, Maintenance Product HVAC urface Decontamination Aseptic Technique Training SOPs Personnel IN/OUT Airflow Patterns Air Supply Room Pressure Adjacent Areas

35 Risk Mitigation -80 % Risk=AxBxCxD= 1,5x1,25x1,5x1= 2,81 Spray & Pray... Risk=AxBxCxD= 1,5x1,25x1,25x1= 2,34 UV+LAF Risk=AXBXCXD= 1,5x1,25x0,25x1 = 0,46 HPV

36 Key features of a decon MAL? Equipment air tightness leak test Turbulence HPV/Air mixture distribution Biocide concentration monitoring Equipment Chamber aeration through HEPA Filter Chamber positive differential pressure (15 Pa during aeration and stand-by phases) Monitoring of Biocide effective removal below TLV requirements Robustness of the unit control system

37 Decontamination cycle 4 PHASE DECONTAMINATION CYCLE 1. Chamber pre-conditioning 2. Load of the Biocide 3. Holding time 4. Aeration

38 Decontamination cycle Chamber preconditioning Biocide load Holding time Aeration % H 2 O % H 2 O WFI/PW

39 Compressed Air Air Heater HP Vaporizer FRESH AIR UDAF integrated into a MAL H14 HEPA (OPTION) H14 HEPA AIR EHAUST Liquid H 2 O 2 HP INLET UDAF HP MIXING FAN M HP CATALYZER H14 HEPA H14 HEPA

40 MAL units examples Surface biodecontamination transfer hatch for heat sensitive products to be delivered into a Class A sterile suite from a Class C area.

Humidity; Temperature; H 2 O 2 concentration; H 2 O 2 distribution uniformity;

41 The right recipe to achieve a process robustness The ingredients of our recipe are the followings: Material and chamber surfaces clean and dry; Relative Humidity; Temperature; H 2 O 2 concentration; H 2 O 2 distribution uniformity; Process lethality and holding time; H 2 O 2 absorption/desorption; Aeration. Key factors

42 PID-based H 2 O 2 vaporizer Process controller Setpoint Control Control loop Measurement Probe

43 New generation H 2 O 2 Vaporizer

44 Chamber tightness Pressure decay test cycle start / cycle end Dual Inflatable gaskets with integral integrity testing DEFLATED INFLATED

Enclosure evaluation Biocide uniformity evaluation

Optimization Biological Performance Qualification Cycle

study Enclosure pressure decay test Enclosure T/RH

Enclosure T mapping with biocide Biocide stratification

value calculation BI worst location identification 3

45 Enclosure evaluation Biocide uniformity evaluation VALIDATION PACKAGE Biological system evaluation & Optimization Biological Performance Qualification Cycle safety evaluation Load pattern study Air distribution study Enclosure pressure decay test Enclosure T/RH mapping HEPA filters leak test Particle counting Enclosure T mapping with biocide Biocide stratification CIs worst location 3 BI s per location Enclosure D- value calculation BI worst location identification 3 time BI s exposure per worst location Aeration time study Biocide TLV analysis 45

46 Key points to note Disposable heat sensitive materials are becoming widely used in aseptic manufacturing; Material transfer has to be design to minimize the risk of microbial contamination, QbD approach; Traditional MAL cannot guarantee a safe and validated transfer into an aseptic suite and cannot be accepted anymore; Surface chemical bio-contamination is now the front edge of the transfer technology; A robust process control takes an important role in the Material Air Lock system reliability.

47 Thank you.

PASSION THAT DRIVES PERFORMANCES. WASHINGSOLUTIONS

PASSION THAT DRIVES PERFORMANCES. WASHINGSOLUTIONS s to on, WASHING SOLUTIONS Fedegari offers a wide range of innovative solutions and full support on cleaning process optimization to meet the most demanding