1. Auditing of sterile production
BY:
PRAKHAR RAI
M.PHARM. (PHARMACEUTICAL QUALITY ASSURANCE)
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Department of Pharmaceutical Sciences & Technology
Birla Institute of Technology, Mesra
Ranchi – 835 215 (Jharkhand)
2. Auditing of sterile production
The products that are going to be infused directly into bloodstream or
body tissues are called sterile product and the method of producing a
sterile product is called sterile production.
Auditing is the systematic examination of a quality system and audits
form an important part of Good Manufacturing Practice (GMP).
Auditors need to be knowledgeable about sterile production.
The auditor should assess what control measures are in place to protect
the process and product from contamination.
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4. Audit considerations
During an aseptic/sterile production audit, the auditor must observe the:
1. Building and works
2. HVAC System
3. Environmental Monitoring
4. Garments
5. Sanitation
6. Equipment
7. Manufacturing Process
8. Sterilization
9. Documentation
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5. Building and works
Whether the building is devoid of cracks especially in the aseptic solutions preparation
rooms, filling rooms, sealing rooms etc.
Are the location of services like water, steam, gases etc. are such that the servicing or
repairs can be carried out without any threat to the integrity of the facility.
Whether the manufacturing areas clearly separated into preparation areas, change areas
and aseptic areas.
Whether the surface joints like electric sockets, gas points flushed with walls and the
air grills and lights flushed within the walls.
Whether doors open towards higher pressure areas and close automatically due to air
pressure.
Whether the aseptic areas have separate exit and entrances.
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6. Building and works cont…
Whether an appropriate inter- locking system with visual and/or audible warning
system installed to prevent the opening of more than one door at a time.
Do the aseptic and non-aseptic areas provided telephones or speak phones for
communication purposes.
Are the rest room, canteen and toilets outside the sterile manufacturing area.
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7. HVAC System
Whether the Air Handling Units for sterile product manufacturing area separate from
those for other areas.
Give the Background Grade of air for following critical areas:
A. Aspectic filling area.
B. Sterilized components unloading area.
C. Filling room of terminally sterilized products Batch manufacturing area.
D. Component washing and preparation area
E. Final Change room (Aseptic Area).
Are the filter configuration in the air handling system suitably designed to achieve the
Grade A, B, C, D and E of air as per designed classified areas.
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8. Environmental Monitoring
Whether the records exist to show that all the environmental parameters were verified
at the time of installation and checked.
Are the recommended periodic monitoring frequencies followed:
a) Particulate counts - 6 Monthly
b) HEPA filters integrity testing - Yearly
c) Air Change rates - 6 Monthly
d) Air pressure differentials - Daily
e) Temperature and Humidity – Daily
Does a written Environmental Monitoring Program exist?
In case of major engineering modifications being carried out to the HVAC system of
any area, Whether all parameters are approved before starting production.
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9. Garments
Whether Outdoor clothing is allowed in the sterile areas.
Do they use cotton garments which are not allowed?
Are the garments made of non-shedding and tight weaving material?
Whether Pockets and belts are avoided.
Whether the personnel wear only clean, sterilized and protective garments at each work
session where aseptic filtration and filling operations are undertaken and at each work
shift for products intended to be sterilized.
Are masks and gloves are changed at every work session.
Are the foot-wear daily cleaned with a bactericide.
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10. Sanitation
Whether written procedures available for sanitation of sterile processing facilities.
Whether distilled water is used for the dilution of the disinfectant.
Whether alcohol or isopropyl alcohol is used as disinfectant for hand sprays?
Whether fumigation carried out in aseptic areas.
Whether an SOP exist for the purpose of fumigation.
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11. Equipment
Are the following equipment available with the sterile product manufacturing facility:
a. Component washing machines.
b. Steam Sterilizers.
c. Dry heat sterilizers.
d. Membrane Filter Assemblies.
e. Manufacturing Vessels.
f. Blenders.
g. Liquid filling Machines.
h. Powder filling Machines.
i. Sealing and labelling Machines.
j. Vacuum testing chambers.
k. Inspection Machines.
l. Lyophilizes.
m. Pressure Vessels.
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12. Manufacturing Process
whether the bulk raw materials and bulk solutions monitored for bio-burden
periodically (solutions not to contain more than 100 cfu/m)
Whether the principle of minimum possible time between the preparation of the
solution and its sterilization or filtration through microorganism retaining filters
followed and also specified in Master formula.
Whether gas cylinders are kept out side of the aseptic areas.
Whether the washed containers sterilized immediately before use.
Sterilization:
Whether the sterilizing processes have been validated( Dry heat, Moist heat, filtration)
Whether significant changes made to the equipment and product. Whether the records
of such changes maintained.
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13. Manufacturing Process cont…
Whether the terminal sterilizer's capacity is sufficient to sterilize one batch completely
at one time.
Whether the position of temperature probes used for controlling and / or recording
determined during validation and been checked against a second independent
temperature probe located in the same position.
Whether recording of both temperature and pressure carried out to monitor the process.
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14. Documentation
Do the manufacturing records pertaining to manufacture of sterile products indicate the
following details:
◦ Serial number of Batch Record
◦ Name of the product
◦ Reference to Master Formula Record
◦ Batch/Lot number
◦ Batch/Lot size
◦ Date of manufacture and assigned date of expiry
◦ Names of all ingredients with grade given by the quality control department.
◦ Time and duration of blending, mixing etc.
◦ Temperature and humidity records whenever applicable.
◦ Results of pyrogen and / or bacterial endotoxin and toxicity
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15. Documentation cont…
◦ Leakage test records.
◦ Inspection records.
◦ Sterilization records including leakage test records, load details, date, duration, temperature,
pressure etc.
◦ Container washing records.
◦ Total number of containers filled.
◦ Total number of containers rejected at each stage.
◦ Whether result of the tests relating to sterility, pyrogens and bacterial endotoxins are
maintained in the analytical records.
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