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Most frequent GMP deficiencies observed in sterile production facilities
Ian Thrussell, MHRA, UK
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
Nanjing, November 2009
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 2 |
Session Outline Session Outline
� Inspection Findings - Aseptic Processing
� Inspection Findings – Terminally sterilised Products
� Questions
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 3 |
Raw Materials
Personnel
Procedures Validated processes
Equipment
Premises
Environment
Packing Materials
Poorly designed processes
Poorly designed processes
� Materials transferred
into Aseptic area with
insufficient sterility
assurance
� Poor transfer of partially stoppered vials to
lyophiliser
� Excessive holding times
for sterile equipment or
filtered solutions
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 4 |
Raw Materials
Personnel
Procedures Validated processes
Equipment
Premises
Environment
Packing Materials
Poorly designed processes
Poorly designed processes
� Single filtration
� Filtration not performed
as close as practicable
to the filling point
� Inadequate response to leaking containers – no
limits set to prompt an
investigation
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 5 |
What happened when these filters are
vented!
What happened when these filters are
vented!
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 6 |
Raw Materials
Personnel
Procedures Validated processes
Equipment
Premises
Environment
Packing Materials
Poorly designed processes
Poorly designed processes
� Raw material suppliers
not audited but
acceptance of side
samples e.g. sterile API
side samples accepted with no justification
� Prefilled syringe
assembly sterilisation
sites never audited
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 7 |
Raw Materials
Personnel
Procedures Validated processes
Equipment
Premises
Environment
Packing Materials
Poor clean room and aseptic practices
Poor clean room and aseptic practices
� Filling needles installed & left
unprotected while remainder of line set up still taking place Not routinely recorded/documented
� No monitoring during equipment set up
� Allowed interventions into aseptic zone are not derived from risk based process review
� Systems/Procedures not clear what to do upon intervention
� Interventions not linked to batch release process
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 8 |
Raw Materials
Personnel
Procedures Validated processes
Equipment
Premises
Environment
Packing Materials
Poor clean room and aseptic practices
Poor clean room and aseptic practices
� Interventions not linked
to batch release process
� Excessive numbers of manipulations
� Excessive numbers of people
� People routinely located in the class A zone
� Failure to use isolation and closed techniques
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 9 |
� “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.”
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 10 |
� 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.
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 11 |
Raw Materials
Personnel
Procedures Validated processes
Equipment
Premises
Environment
Packing Materials
Poorly designed or maintained equipment
Poorly designed or maintained equipment
� Viewing ports on
sterilising tunnels not
adequately sealed
� Lyophilisers not
sterilisable or not sterilised sufficiently
frequently
� Vial capping performed
under uncontrolled
conditions
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 12 |
Construction activities 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
� Media Fill Failure 2 weeks later
– Construction not considered to be the cause. Root causes identified
by investigation considered corrected.
� New Media Fill performed
� Second Media Fill Failure Occurred
� Contamination attributed to construction
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 13 |
Examples of misplaced stoppers from real case
lines
Examples of misplaced stoppers from real case
lines
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 14 |
Vision systems for raised stopper detection Vision systems for raised stopper detection
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 15 |
Raw Materials
Personnel
Procedures Validated processes
Equipment
Premises
Environment
Packing Materials
Poorly designed or maintained equipment
Blow fill seal machine
Poorly designed or maintained equipment
Blow fill seal machine
� Cooling water – Chills mold plates used to form the
container-closure into which the sterile drug is filled.
– Demineralized potable water. Held in tank, chilled (when sampled, yields very high microbial counts)
� Sterility failure and media fill failure
– 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 machine’s mold plates. Cooling water directly contaminated product.
– CAPA Issue: Exact date of problem occurrence unknown.
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 16 |
Raw Materials
Personnel
Procedures Validated processes
Equipment
Premises
Environment
Packing Materials
Poorly designed or executed PM monitoring
Poorly designed or executed PM monitoring
� Samples points
inappropriately
positioned
� Alarm systems do not
feedback to filling operators.
� Alarms and procedures
unclear and confused
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 17 |
Raw Materials
Personnel
Procedures Validated processes
Equipment
Premises
Environment
Packing Materials
Poorly designed or executed PM monitoring
Poorly designed or executed PM monitoring
� Length of tubing to
particle counter too long
& even kinked!
� PMS data not reviewed
as part of batch release process
� Overseas-use of
manifold systems and
no 5 micron monitoring
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 18 |
Raw Materials
Personnel
Procedures Validated processes
Equipment
Premises
Environment
Packing Materials
Poorly designed or executed PM monitoring
Poorly designed or executed PM monitoring
� Reliance on the use of
contact plates and no use of swabs
� Reliance on active air monitoring and inadequate use of settle plates
� “Averaging into compliance” – inadequate attention to the individual high count
� Acceptance of “good pattern” of very low contamination and failure to evaluate whether the programme is effective.
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 19 |
Raw Materials
Personnel
Procedures Validated processes
Equipment
Premises
Environment
Packing Materials
Poorly designed or executed micro monitoring
Poorly designed or executed micro monitoring
� Viable sample points not
close to point of fill
� The whole process is not monitored
� Viable sampling does not cover all key areas under Grade A e.g. vial turntable, stopper hopper
� Monitoring is not risked based and “too routine”
� High pre-filtration bioburden not adequately investigated and bioburden limits >> 10cfu/100ml and no justification
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 20 |
Raw Materials
Personnel
Procedures Validated processes
Equipment
Premises
Environment
Packing Materials
Media fills! 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
� Poor practices accepted as covered & justified by “passing” Media Fills!
� Good history does not mean failures/growth need not be investigated
� Implications to batches on the market or in stock subsequent to failures are not always considered fully
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 21 |
Raw Materials
Personnel
Procedures Validated processes
Equipment
Premises
Environment
Packing Materials
Media fills! Media fills!
� Interventions allowed in
procedures but not
covered by simulations
� Excessive interventions
not prohibited
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 22 |
Raw Materials
Personnel
Procedures Validated processes
Equipment
Premises
Environment
Packing Materials
Steam Sterilisation! 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
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 23 |
Raw Materials
Personnel
Procedures Validated processes
Equipment
Premises
Environment
Packing Materials
Steam Sterilisation! Steam Sterilisation!
� Long heat times during
validation not
investigated as no limits
for heat up times =
potential sterility issues
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 24 |
When sterilising equipment and components -
there is just one objective
� TO KNOW UNEQUIVOCALLY THAT ALL PARTS OF
THE LOAD ARE SUBJECT TO DRY SATURATED
STEAM AT THE REQUIRED TEMPERATURE FOR
THE REQUIRED TIME.
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 25 |
A sterilization process based on the principle that cold air within the chamber is
heavier than the steam entering and will sink to the bottom of the chamber. As
steam enters the chamber, air is pushed out the bottom drain and exits, with the
condensate, through a steam trap.
Gravity Displacement Process
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 26 |
Equilibration Time 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.
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 27 |
Sterilization Process Development
Equilibration Time
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 28 |
1 Prevacuum - Tyvek Wrapped Materials l
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
Deg C
Time
TC1 Drain
TC 5
TC 6
TC 7
TC 8
TC 9
TC 10
TC 11
TC 12
TC 13
TC 15
TC 16
TC 17
TC 18
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 29 |
� 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.
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 30 |
Pre-vacuum Process 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.
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 31 |
Raw Materials
Personnel
Procedures Validated processes
Equipment
Premises
Environment
Packing Materials
Steam Sterilisation & SIP systems! Steam Sterilisation & SIP systems!
� Air removal from equipment
not adequately considered
� Steam quality not assessed
adequately
– Non-condensable gases
– Wet steam (Dryness
fraction)
– Superheat Clean steam
quality tests are not
performed at distal points of the distribution system.
Steam quality test not performed following
modifications
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 32 |
Raw Materials
Personnel
Procedures Validated processes
Equipment
Premises
Environment
Packing Materials
Oven designs! Oven designs!
� No overpressure in hot
air ovens
� No HEPA filters on the
exhaust side of the oven
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 33 |
Raw Materials
Personnel
Procedures Validated processes
Equipment
Premises
Environment
Packing Materials
Packaging and post sterilisation damage! Packaging and post sterilisation damage!
� Failure to meet GMP:
– Rough handling of bulk finished vials resulted in difficult to detect and hairline cracks in bottle. “Washdown” of vials with potable water was apparent contamination source.
� Patients Infected: multiple blood cultures yield Enterobacter cloacae.
� At least one lot “directly implicated” in septicemia
� Over 25 Septicemia Reports naming the lot or “unknown”
� Class 1 Recall: Eleven Lots (“strong likelihood that product will cause serious adverse health consequences or death”)
� Cultures of unopened vials grew Enterobacter cloacae
� 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 34 |
Raw Materials
Personnel
Procedures Validated processes
Equipment
Premises
Environment
Packing Materials
Sterile API – unacceptable process design!Sterile API – unacceptable process design!
� Huge Grade A/B rooms-
poor differential
pressures
� Masses of pipe work
� Redundant equipment
� Cracks, crevices,
ledgesKK.
� Sterility starts here!
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 35 |
Bulk lyophilisation Bulk lyophilisation
Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors
Nanjing, November 2009 36 |
Risk of contamination
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 37 |
� Orchid Video
� E:\Training Materials\Bulk Lyophilisation Videos\Bulk
Lyophilisation\Orchid videos\LYO Unloading - 3 (Frames 21-
26).mpg
� Qilu Video
� E:\MHRA BAck ups\MHRA Laptop back ups\16_11_09\MHRA
Documents\Qilu Autoloading\Video for unloading-
20081210160000[4].dav