FDA Guide To Aseptic

Processing
• Or: ‘Guidance for Industry Sterile Drug
Products Produced by Aseptic Processing
— Current Good Manufacturing Practice’
• First issued in 1987
• New version September 2004
• Applies to pharmaceutical manufacturers
operating in or exporting to North America
• Different to EU GMP, pharmacopoeias (USP, EP,
JP), CFRs
 Main Content
•90% microbiological or microbiologically related
•Includes:
•HVAC
•Personnel
•Components
•Endotoxin control
 Main Content
• Also:
– Time expiry
– Media (‘broth’) trials
– Filtration
– Sterilization
– Microbiology laboratories
– Environmental Monitoring
– Sterility testing
• These are the ‘chapter’ headings
 HVAC
• Includes ‘guidance’ limits
• Uses ISO terminology for clean rooms (5, 7 and 8  A,
B and C. Note: No equivalent to Grade D exists)
• Considers 0.5m particles only (5.0 m are not
important – unlike EU GMP)
• Sets limits for active air-samples and settle plates
which equal or exceed those of EU GMP, although:
“Air monitoring samples of critical areas should
normally yield no microbiological contaminants”
 HVAC
• Airflow studies are mandatory for Grade A
and B including interventions. Must be
videotaped.
• Defines pressure differentials; HEPA filter
design; construction of clean rooms.
Recommends Isolator Technology.
• States interventions should be mechanical
where possible.
 Personnel
• The following training is mandatory and is
to include Microbiology staff: aseptic
technique, cleanroom behaviour,
microbiology, hygiene, gowning, patient
safety hazards posed by a non-sterile drug
product
 Personnel
• Advice on working in Aseptic Filling
facilities is laid out:
• Only using sterile objects to touch critical surfaces
• Moving slowly and deliberately as not to disrupt
UDAF
• Always approach critical areas from the side
• Proper gowning including regular audit and daily
contact plates of gloves, facemask, arms and chest
 Components
• The biggest risk is endotoxin – emphasis on
cleaning, drying and storage of equipment
• Depyrogenation studies to cause a 99.9%
reduction of endotoxin for dry heat or WFI
rinsing
 Validation of Aseptic Filling
• Media simulation studies
• Minimum of six monthly
• Must be the biggest possible batch size; include
lyophilisation; maximum number of personnel;
shift breaks and gown changes; vary line speeds
• Soyabean casein digest medium with evaluation
with environmental isolates
• Inspection overseen by the “QC Microbiologist”
 Filtration
• Sterilising grade filters must be evaluated
• Use Brevundimonas diminuta (ATCC
19146) at 107 per cm2.
• Vary viscosity; pH; flow rate; pressure;
time; temperature; osmorality; hydraulic
shock
 Sterilisation
• Validation of load cycles in sterilisation
devices.
• Measure time and temperature
• Use Biological Indicators or Endotoxin
Indicators depending upon moist or dry heat
 Environmental Monitoring
• Must have a written rationale
• Samples taken in dynamic state and must
relate to an activity
• Include critical surfaces e.g. filling needles
• Must set alert and action levels based on
historical data
 Environmental Monitoring
• SOPs must include:
1) frequency of sampling, (2) when the samples are
taken (i.e., during or at the conclusion of
operations), (3) duration of sampling, (4) sample
size (e.g., surface area, air volume), (5) specific
sampling equipment and techniques, (6) alert and
action levels, and (7) appropriate response to
deviations from alert or action levels.
 Environmental Monitoring
• Must perform trend analysis for monitoring
and personnel data
• Must examine daily, weekly, monthly,
quarterly and longer time periods
• Must profile microbiological flora
 Environmental Monitoring
• Must qualify disinfectants especially
contact time
• Must use the correct disinfectant for the
process e.g. sporicidal
 Environmental Monitoring
• Must validate monitoring methods
• Surface samples (must monitor walls and ceilings)
• Active air samples (most critical; must show airflow
disruption)
• Settle plates (not important in their own right –
unlike EU GMP – but useful if used to support
active air; must perform desiccation experiments)
 Environmental Monitoring
• Must perform identifications from Grade A
and B to species level
• Sterility test failures must be identified
using genotypic techniques (not phenotypic
techniques)
 Environmental Monitoring
• Each incoming lot of media must be tested
for growth promotion
• Particle counting must be performed
 Sterility testing
• The test must be validated
• Samples must be from start, middle and
end, and to include interventions
• A confirmed failure is to result in batch
rejection
 Other areas
• Prefiltered solutions must be assessed for
total viable count
• Expiry time setting of equipment
• The importance of a microbiological batch
review (to be of wide scope and include
WFI results; assessment of interventions;
early process stage samples)
 FDA opt-out
• It “contains non-binding recommendations”
i.e. and inspector can add anything else that
is cGMP
• This can include 21 CFR 210 and 211; ISO;
AOAC; USP
• It won’t include EU GMP; EMEA; PIC/S
(yet); TCA; Ph. Eur.
 End

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