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CONSIDERATIONS:
Design Requirements for Facilities and
Equipment and Their Qualification – A
Case Study
Tunnel sterilizer:
• Operates continuously.
• Ideal for large load sizes.
• Fast processing time.
• Convection, infrared,
flame sterilizers.
• Variable heating zones.
• Airflow opposite product flow. PDA Technical Monograph #3
Dry Heat Depyrogenation – Facilities Considerations
• Integration / Process flow – How is the integration
of depyrogenation oven with other equipment such
as vial washers, filling and capping machines,
packaging equipment, etc. to be realized such that
uninterrupted processing may be achieved?
• Total process throughput is tied to rate limiting
step. Select oven and validate depyrogenation
cycle time appropriate to overall manufacturing
process.
Dry Heat Depyrogenation - Facilities Considerations
• Capacity – Does the oven have sufficient capacity to
meet current and future processing needs?
• Classification – Is the classification of the oven
compatible with the classification of the area where it
will located and the overall manufacturing process?
Most depyrogenation ovens are rated Class 100 and
should therefore be suitable for application in vial
and equipment prep areas of aseptic manufacturing
facilities.
Dry Heat Depyrogenation – Facilities Considerations
• HVAC / Utilities – Are current HVAC controls and
utilities (electrical, water, air) adequate to meet the
needs of the depyrogenation oven? How much
added stress will be placed on the existing HVAC
system and utility supply and what impact will this
have on the operation of other equipment ?
• Installation – Are the dimensions of the oven such
that it can be transported to and installed in the
desired location or will alterations to the facility and
existing layout be necessary?
Dry Heat Depyrogenation – Facilities Considerations
Gruenberg L55H8.3PTSS:
• Chamber interior:
– 20” x 30” x 24” (8.3 ft3/ 0.2 m3).
• Chamber exterior:
– 68” x 44” x 70”.
• Bio sealing flange.
• Horizontal flow of heated Class
100 HEPA filtered air.
• Heat exchanger (cold water) for
cool down.
http://www.epsovens.com
Dry Heat Depyrogenation – Case Study
Gruenberg L55H8.3PTSS:
• Temperature range:
– Max. 280 oC.
– Operating 250 oC.
• Temperature Control:
– 0.25% of scale at 250 oC.
– Ramp rate > 1.5 oC/min.
• Temperature uniformity:
– + 5 oC at 250 oC. http://www.thermalproductsolutions.com
Dry Heat Depyrogenation – Validation
• EP 5.1.1 General Texts on Sterility.
• USP <1211> Sterilization and Sterility Assurance.
• EMEA: Decision Trees for sterilization.
• ISO 14937 – General requirements for sterilization.
• PDA TR 3 – 1981 Dry Heat Processes for sterilization
and depyrogenation; revision 2008.
• PDA TR 7 – Depyrogenation.
• FDA Aseptic Processing Guidelines 2004.
• AAMI ST63 – 2002 Dry Heat sterilization.
• HTM 2010 and other regional requirements.
Dry Heat Depyrogenation - Validation
Documentation:
• Validation Master Plan.
• User Requirements Specification (URS).
• Request for Quote (RFQ).
• Proposal from vendor (including drawings).
• Functional / Design Specifications.
• Factory Acceptance Test (FAT).
• Validation Documentation (IQ/OQ/PQ).
Dry Heat Depyrogenation – Validation
General Validation Strategy:
• Factory Acceptance test (FAT).
• Installation Qualification (IQ).
• Operational Qualification (OQ) – 3 cycles.
• Cycle Development / Heat Penetration (HP) studies.
• Reduced Cycle testing – 1 cycle.
• Performance Qualification Testing (PQ) – 3 cycles.
• Annual revalidation – One ea. OQ and PQ cycle.
Dry Heat Depyrogenation – FAT
Factory Acceptance Test:
• Verify physical dimensions of unit.
• Verify loading system operates correctly.
• Verify access ports for particle testing.
• Conduct heat distribution test (empty chamber).
• Conduct load test.
• Verify proper ∆ P across HEPA filters.
• Personnel training in operation of unit.
Dry Heat Depyrogenation – IQ
Installation Qualification (IQ):
• “Obtaining and documenting evidence that
equipment has been provided and installed in
accordance with its specification.” ISO 14937:2002.
• Do we have all the parts?
• Will the unit fit into the allotted space?
• Do we have the necessary utilities?
• Is the unit to spec?
Dry Heat Depyrogenation – IQ
Particle counts:
• Clean oven with IPA and lint-free wipes.
• Sample from open end of 10 mm SS tubing
placed at center of HEPA filter. Communicate
tubing to exterior of chamber via sanitary adapter
fitting and connect to particle counter. Measure
every 10 minutes at flow rate of 1 CFM.
• Performance consistent with Manufacturer's
specifications and intended application.
Dry Heat Depyrogenation – OQ
Chamber Pressure:
• Measure pressure of chamber during cycle via
sanitary port.
• Cycle temperature set at ambient to avoid injury.
• Differential pressure of > 0.03” W.C. relative to
atmospheric as per Manufacturer's specifications.
Dry Heat Depyrogenation – OQ
Confirm documentation:
• Verify successful IO/OQ
with signed report.
• Verify approved SOPs for
operation and cleaning.
• Verify maintenance and calibration schedule.
• Verify spare parts entered into facility’s system.
• Assemble all vendor related documentation.
Dry Heat Depyrogenation – HP
Cycle Development/Heat Penetration Studies:
• Prepare maximum load pattern.
• Calculate cycle parameters for desired process
conditions and application.
• Consider each item’s mass, complexity, cavities,
composition, density, etc.
• Place thermocouples in chamber and within load to
determine slow-to-heat zones within items being
processed. Thermocouples to be placed in slow-to-
heat zones during subsequent PQ testing.
Dry Heat Depyrogenation – Endotoxin Challenge
Endotoxin indicators:
• Prepared from CSE.
• > 1000 EU (50 – 200% var.).
• Direct product inoculation preferred but may (will)
present recovery issues.
• Usually prepared in 5 -10 sealed glass vials (ECV)
placed within load at cold spots.
• Positive and Negative controls.
Dry Heat Depyrogenation – Reduced Cycle
t (T – Tb)/Z
FH = 0 ∫ 10 dt
where:
t = time at end of hold period.
T = temperature (actual temperature).
Tb = baseline temperature (250 oC).
Z = z-value of endotoxin (46.41 – 54 oC2).
1Tsuji and Harrison. 1978. Appl. Environ. Mbio. 36(5): 710-713.
2Akers et. Al.1982. J. Parent. Sci. Technol. 36(1):23-27.
Dry Heat Depyrogenation – PQ
Calculate endotoxin log reduction value: