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: These are the ‘chapter’ headings 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 Any Questions?