Cycle Development and Validation Guidance for Vaporized Hydrogen Peroxide (VHP) Low Temperature Surfaces Terminal Sterilization Processes
Juha Mattila Senior Product Manager STERIS Finn-Aqua
03.09.2015 ISPE Nordic Conference – Advanced Aseptic Processing 1 1/ Presentation content
• Vaporized Hydrogen Peroxide (VHP) • VHP low temperature surfaces sterilization process principle • Applications • Cycle development and validation guidance
03.09.2015 ISPE Nordic Conference – Advanced Aseptic Processing 2 2/ Vaporized Hydrogen Peroxide (VHP)
• Low temperature dry vapour process (remains below dew point) • Long established sterilant for full spectrum of biological contaminants • Compatible with a wide variety of materials • No penetration to product, no materials discoloration • Breaks down to water vapour and oxygen
03.09.2015 ISPE Nordic Conference – Advanced Aseptic Processing 3 3/ VHP low temperature surfaces sterilization process principle
03.09.2015 ISPE Nordic Conference – Advanced Aseptic Processing 4 4/ VHP low temperature surfaces sterilization process principle
• Pre-conditioning • Exposure • Post-conditioning
03.09.2015 ISPE Nordic Conference – Advanced Aseptic Processing 5 5/ Process graph
• Typical process temperature +28…40 °C • Typical cycle time 2…4 hours, depending on product, load config and materials • Deep vacuum process (1…10 mbar level) 03.09.2015 ISPE Nordic Conference – Advanced Aseptic Processing 6 6/
• Air / vacuum • Peroxide • Humidifying pulses injections pulses (3-5) • Load heating (35%) • Forced air up (if required) • VHP hold • Equalization • Deep • VHP injection vacuum: 1...4 to maintain mbar target humidity 20- • Steam injection 60- 40- 40 • Steam hold 90 110 min min min VHP Process limitations
•VHP is a surface sterilant. •Wet surfaces will affect the process •Load Temperature should be within reasonable limits (not directly from cold storage) •Works well with Tyvek and plastics. No Cellulose, cotton or highly absorptive materials.
03.09.2015 ISPE Nordic Conference – Advanced Aseptic Processing 7 7/ Applications
03.09.2015 ISPE Nordic Conference – Advanced Aseptic Processing 8 8/ VHP Low Temperature Surfaces Terminal Sterilization
• In-house processing • For temperature / radiation sensitive products • Low Temperature VHP sterilization in vacuum (controlled environment!) • Sterilized surfaces of device exterior and package interior (example: ophthalmic parenteral drug products) • Typical production chamber sizes 0.5…10 m³ • 2…4 hours complete cycle time
03.09.2015 ISPE Nordic Conference – Advanced Aseptic Processing 9 9/ Typical drug product applications
• Complex delivery devices, pre-filled syringes, vials • E.g. protein-based drugs, hyaloronic acid, mixed substances, biologics, biosimilars • Single-packaged in TYVEK or equivalent • To claim entire packaged product sterility • To simplify manufacturing and packaging process
03.09.2015 ISPE Nordic Conference – Advanced Aseptic Processing 1010 / VHP Low temperature sterilization applications
Taking packaging from the clean room to a more controlled and repeatable process
03.09.2015 ISPE Nordic Conference – Advanced Aseptic Processing 1111 / VHP distribution / penetration
• VHP vapor penetrates TYVEK layer • Reaches dead legs
03.09.2015 ISPE Nordic Conference – Advanced Aseptic Processing 1212 / Application example – Mixing device
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03.09.2015 ISPE Nordic Conference – Advanced Aseptic Processing 1313 / Application example - Vials
03.09.2015 ISPE Nordic Conference – Advanced Aseptic Processing 1414 / Typical single-packaged product
03.09.2015 ISPE Nordic Conference – Advanced Aseptic Processing 1515 / Typical products by category
Wrapped Vials
Syringes, Hyaloronic acid based products
Syringes, Ophthalmic drug products
Wound Care Dispenser Devices
Pre-Injection Mixing Devices (combining components)
Packaged towel products
03.09.2015 ISPE Nordic Conference – Advanced Aseptic Processing 1616 / Cycle development and validation guidance
03.09.2015 ISPE Nordic Conference – Advanced Aseptic Processing 1717 / Step-by-step approach to implementing VHP low temperature surfaces sterilization process
03.09.2015 ISPE Nordic Conference – Advanced Aseptic Processing 1818 / Product feasibility testing
- Verify material compatibility with VHP (no color change etc.) - Product integrity tests (plunger movement, deep vacuum level, no leaks to primary container => no contact to drug product) - Use smaller amount of product samples - Chemical indicators to show reaching inside blister/TYVEK® package - Intial tests for reaching 10E6 kill (biological indicators) - Verify package compliance (TYVEK® pass-through both ways)
03.09.2015 ISPE Nordic Conference – Advanced Aseptic Processing 1919 / Load Cycle Development
Cycle development tests using actual production unit and sample loads => Initial optimization and parameters to benefit the final validated cycle
03.09.2015 ISPE Nordic Conference – Advanced Aseptic Processing 2020 / Defined repeatable load quantities and loading patterns
• Defined load configurations for cycle repeatability and validation
03.09.2015 ISPE Nordic Conference – Advanced Aseptic Processing 2121 / Cycle Development and validation indicators
Chemical indicators Biological indicators prove show VHP coverage sterilization efficacy and presence in load (6-log CFU overkill of Bacillus and chamber Stearothermophilus
CYCLE DEVELOPMENT CYCLE DEVELOPMENT AND ONLY VALIDATION
03.09.2015 ISPE Nordic Conference – Advanced Aseptic Processing 2222 / Load mapping for cycle development
IV II III I Front of Chamber, Left Side Rear of Chamber, Left Side Front of Chamber, Right Side Rear of Chamber, Right Side A B A B A B A B 5 11 1 1 15 31 1 6 12 2 2 11 21 1
3 3
4 4 32 22 2 2 5 5 16 12
6 6 33 7 11 23 3
1 7 17 13 7 18 2 4 8 8 34
9 9 17 14 24 3
10 10 13 11 11 8 25 5 35 14 12 12 1 15 2 3 12 4 1 7 13 13 36 18 6 8 14 14 16 26
15 15 37 7
16 16 17 27
17 17 19 5 19 3 18 18 38 9 13 8 20 4 19 19 18 28 20 20 39 9
21 21 20 19 29 6
22 22 20 14 9 15 23 23 40 10 30 10 10 16
Biological Indicator Chemical Indicator RH Sensor Temperature Sensor
03.09.2015 ISPE Nordic Conference – Advanced Aseptic Processing 2323 / Challenging the packaged device
• Using actual product packages for cycle verification and challenge – place indicators inside and re-seal TYVEK for cycle
03.09.2015 ISPE Nordic Conference – Advanced Aseptic Processing 2424 / Challenging the packaged device
• Chemical indicator placed inside re-sealed packaged item
03.09.2015 ISPE Nordic Conference – Advanced Aseptic Processing 2525 / Challenging the packaged device
• Biological TYVEK-enveloped indicator placed inside re-sealed TYVEK- packaged item
03.09.2015 ISPE Nordic Conference – Advanced Aseptic Processing 2626 / Validation guidance - ISO 14937:2009 – ”Sterilization of health care products – general requirements for characterization of a sterilizing agent and the development, validation and routine control of a sterilization process for medical devices” - For health care products but not limited to – applicable to be used as basis for validation for VHP low temperature surfaces sterilization process - First two steps of feasibility testing and load cycle development testing well documented provide good basis for validation - The surface sterilization process to be capable of delivering a Sterility Assurance Level (SAL) of 10-6 as it is defined in the annex of the standard - Biological indicators used in validation cycles - Sterility Assurance Level (SAL) ISO TS Technical Specification 11139:2006
27/ 03.09.2015 ISPE Nordic Conference – Advanced Aseptic Processing 27
RECENT DEVELOPMENTS
• USP 1229.11 effective August 1, 2015 defines: VAPOR PHASE STERILIZATION
• - Includes VHP (H2O2), peracetic acid, formaldehyde and glutaraldehyde • - VHP is a sterilant and can be validated as surface sterilization process • - The need to prove environment control - temperature, humidity, concentration, vacuum level • -The need to prove process consistency and repeatability - Need to prove 10E6 overkill by BI’s - establishing probability for process is recommended - Empty chamber / full load / half cycle / full cycle considerations - Product integrity and materials feasibility
03.09.2015 ISPE Nordic Conference – Advanced Aseptic Processing 2828 / Thank You! Questions?
03.09.2015 ISPE Nordic Conference – Advanced Aseptic Processing 2929 /