1. 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

2. Main Content 90% microbiological or microbiologically related
Includes:
HVAC
Personnel
Components
Endotoxin control

3. 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

4. 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”

5. 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.

6. 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

7. 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

8. 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

9. 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”

10. 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

11. Sterilisation Validation of load cycles in sterilisation devices.
Measure time and temperature
Use Biological Indicators or Endotoxin Indicators depending upon moist or dry heat

12. 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

13. 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.

14. 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

15. Environmental Monitoring
Must qualify disinfectants especially contact time
Must use the correct disinfectant for the process e.g. sporicidal

16. 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)

17. 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)

18. Environmental Monitoring
Each incoming lot of media must be tested for growth promotion
Particle counting must be performed

19. 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

20. 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)

21. 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.

22. End
Any Questions?