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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors, Nanjing, November 2009
Session Outline
Inspection Findings - Aseptic Processing
Inspection Findings Terminally sterilised Products Questions
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Poor transfer of partially stoppered vials to lyophiliser Excessive holding times for sterile equipment or filtered solutions
Packing Materials
Environment
Premises
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Filtration not performed as close as practicable to the filling point Inadequate response to leaking containers no limits set to prompt an investigation
Packing Materials
Environment
Premises
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Packing Materials
Environment
Premises
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Environment
Premises
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Packing Materials
Environment
Premises
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Any intervention or stoppage during an aseptic process can increase the risk of contamination. The design of equipment used in aseptic processing should limit the number and complexity of aseptic interventions by personnel.
Even successfully qualified systems can be compromised by poor operational, maintenance, or personnel practices.
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Aseptic processing operator touches floor when picking up settle plates, sanitizes hands, and then performs intervention immediately afterward
Operator removes sterile forceps from aseptic processing zone (Class 100), carries them through the surrounding Class 10,000 area, and places them on a trolley in the class 10,000 room. These were the only sterile forceps sterilized and available for aseptic manipulations. Later, the operator retrieves forceps and uses them again at the aseptic processing line to manipulate sterile product.
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Packing Materials
Environment
Premises
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Construction activities
Major construction in cleanroom next to personnel entry airlock (e.g., gowning).
Construction occurred over approximately one-month period and coincided with continued production
New Media Fill performed Second Media Fill Failure Occurred Contamination attributed to construction
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Pseudomonas, sp. and Acinetobacter, sp. found in media fill Stenotrophomonas maltophilia identified as Sterility Failure isolate
Several lots rejected
Both the sterility failure and media fill failure attributed to cooling water contamination Root cause of non-sterility was leak/s/ in aseptic filling machines mold plates. Cooling water directly contaminated product. CAPA Issue: Exact date of problem occurrence unknown.
Packing Materials
Environment
Premises
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Packing Materials
Environment
Premises
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Packing Materials
Environment
Premises
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Acceptance of good pattern of very low contamination and failure to evaluate whether the programme is effective.
Packing Materials
Environment
Premises
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Environment
Premises
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Media fills!
The belief that some contamination is OK! Acceptance criteria does not meet Annex 1 & allows 1 failure to be accepted with no effective investigation Personnel Validated processes Procedures
Packing Materials
Environment
Premises
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Media fills!
Interventions allowed in procedures but not covered by simulations Excessive interventions not prohibited
Personnel Validated processes Procedures
Packing Materials
Environment
Premises
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Steam Sterilisation!
Leak test/Bowie Dick test not performed sufficiently frequently on equipment sterilisers and failures fully investigated. Poor control of checking acceptability of autoclave cycles Engineering work not recorded No trial runs after major breakdowns to show autoclave still meets validated parameters
Packing Materials Personnel Validated processes Procedures
Environment
Premises
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Steam Sterilisation!
Long heat times during validation not investigated as no limits for heat up times = potential sterility issues
Personnel Validated processes Procedures
Packing Materials
Environment
Premises
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
TO KNOW UNEQUIVOCALLY THAT ALL PARTS OF THE LOAD ARE SUBJECT TO DRY SATURATED STEAM AT THE REQUIRED TEMPERATURE FOR THE REQUIRED TIME.
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Equilibration Time
The equilibration time is the period that elapses between attainment of the minimum specified sterilizing temperature in the chamber (chamber reference temperature - typically in the drain) and attainment of the minimum specified sterilization temperature in the load, as measured by the slowest-to-heat penetration probe. This period is an indication of the ability to properly condition the load through air removal and load heating.
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Equilibration Time
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
TC1 Drain
125 124 123 122 121 120 119 118 117 116 115 114 113 112 111 110
TC 5 TC 6 TC 7 TC 8
TC 9
TC 10
Deg C
TC 11
TC 12 TC 13 TC 15 TC 16
TC 17
TC 18
Time
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Short equilibration times can be achieved with appropriate pre-vacuums to pre-condition (remove air and heat) the load.
With appropriate load preconditioning, any surface temperature measurement method should yield acceptable results.
With minimal load pre-conditioning, the heat penetration probes covered with autoclave tape were influenced the most.
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Pre-vacuum Process
A sterilization process in which air is removed from the chamber using a vacuum pump or other mechanical system before the exposure phase begins. This method is particularly suited to load items that can trap air such as tubing, filters and filling machine assemblies.
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Non-condensable gases Wet steam (Dryness Raw Materials fraction) Superheat Clean steam quality tests are not performed at distal points of the distribution system. Packing Materials Steam quality test not performed following modifications Premises
Equipment
Environment
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Oven designs!
No overpressure in hot air ovens No HEPA filters on the exhaust side of the oven
Validated processes Procedures Personnel
Packing Materials
Environment Premises
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Class 1 Recall: Eleven Lots (strong likelihood that product will cause serious adverse health consequences or death)
Cultures of unopened vials grew Enterobacter cloacae
Packing Materials
Environment Premises
Several water samples collected at firm from the water hose/sink found Enterobacter cloacae
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
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Environment
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Bulk lyophilisation
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
Risk of contamination
Extent of human manipulation of sterilised filtrate and lyophilisate during loading and unloading of the large number of trays typically used in these processes. Extent of exposure of sterilised filtrate to controlled environmental conditions during filling, lyophilisation and unloading of lyophiliser compared to lyophilisation in the final container. Extent of aseptic operations subsequent to the sterilisation step at both drug substance and finished product manufacturer in the open tray process compared to lyophilisation in the final container.
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009
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Orchid Video E:\Training Materials\Bulk Lyophilisation Videos\Bulk Lyophilisation\Orchid videos\LYO Unloading - 3 (Frames 2126).mpg
Qilu Video E:\MHRA BAck ups\MHRA Laptop back ups\16_11_09\MHRA Documents\Qilu Autoloading\Video for unloading20081210160000[4].dav
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, November 2009