GMP MANUFACTURING ENVIRONMENT
8. Commissioning, qualifi cation and maintenance
8.3 Maintenance
81
8.2.16 A narrow range of relative humidities coupled with a wide range of temperatures is unacceptable as changes in temperature will automatically give rise to variations in the relative humidity.
8.2.17 For a pharmaceutical facility, based on a risk assessment, some of the typical HVAC system parameters that should be qualifi ed may include:
— temperature
— relative humidity
— supply air quantities for all diffusers
— return air or exhaust air quantities
— room air change rates
— room pressures (pressure differentials)
— room airfl ow patterns
— unidirectional fl ow velocities
— containment system velocities
— HEPA fi lter penetration tests
— room particle counts
— room clean-up rates
— microbiological air and surface counts where appropriate
— operation of de-dusting
— warning/alarm systems where applicable.
8.2.18 The maximum time interval between tests should be defi ned by the manufacturer. The type of facility under test and the product level of protec- tion should be considered.
Note:Table 3 gives intervals for reference purposes only. The actual test periods may be more frequent or less frequent, depending on the product and process.
8.2.19 Periodic requalifi cation of parameters should be done at regular intervals, e.g. annually.
8.2.20 Requalifi cation should also be done when any change, which could affect system performance, takes place.
8.2.21 Clean-up or recovery times normally relate to the time it takes to
“clean up” the room from one condition to another, e.g. the relationship between “at-rest” and “operational” conditions in the clean area may be used as the criteria for clean-up tests. Therefore, the clean-up time can be expressed as the time taken to change from an “operational” condition to an
“at rest” condition.
8.3.3 HEPA fi lters should be changed either by a specialist or a trained person.
8.3.4 Any maintenance activity should be assessed critically to determine any impact on product quality including possible contamination.
8.3.5 Maintenance activities should normally be scheduled to take place outside production hours, and any system stoppage should be assessed with a view to the possible need for requalifi cation of an area as a result of an interruption of the service.
Part A: schedule of tests to demonstrate compliance (for reference purposes only)
Schedule of tests to demonstrate continuing compliance Test parameter Clean room
class
Max. time interval
Test procedure
Particle count test (Verifi cation of cleanliness)
All classes 6 months Dust particle counts to be carried out and printouts of results pro- duced.
No. of readings and positions of tests to be in accordance with ISO 14644-1 Annex B
Air pressure difference (To verify absence of cross-contamination)
All classes 12 months Log of pressure differential readings to be produced or critical plants should be logged daily, preferably continuously. A 15 Pa pressure dif- ferential between different zones is recommended.
In accordance with ISO 14644-3 Annex B5*
Airfl ow volume (To verify air change rates)
All classes 12 months Airfl ow readings for supply air and return air grilles to be measured and air change rates to be calculated.
In accordance with ISO 14644-3 Annex B13*
Airfl ow velocity
(To verify laminar fl ow or containment conditions)
All Classes 12 Months Air velocities for containment sys- tems and laminar fl ow protection systems to be measured.
In accordance with ISO 14644-3 Annex B4*
83 Part B: recommended optional strategic tests (ISO 14644)
Schedule of tests to demonstrate continuing compliance Test parameter Clean room
class
Max. time interval
Test procedure
Filter leakage tests (To verify fi lter integrity)
All classes 24 months Filter penetration tests to be carried out by a recognized authority to demonstrate fi lter media and fi lter seal integrity. Only required on HEPA fi lters. In accordance with ISO 14644-3 Annex B6*
Containment leakage (To verify absence of cross-contamination)
All classes 24 months Demonstrate that contaminant is maintained within a room by means of:
• airfl ow direction smoke tests
• room air pressures.
In accordance with ISO 14644-3 Annex B4*
Recovery (To verify clean- up time)
All classes 24 months Test to establish time that a clean room takes to return from a con- taminated condition to the specifi ed clean room condition. This should not take more than 15 min. In accor- dance with ISO 14644-3 Annex B13*
Airfl ow visualization (To verify required airfl ow patterns)
All classes 24 months Tests to demonstrate airfl ows:
• from clean to dirty areas
• do not cause cross-contamination
• uniformly from laminar fl ow units.
Demonstrated by actual or video- taped smoke tests.
In accordance with ISO 14644-3 Annex B7*
TSR2006_Annexs1_5.indd 83
TSR2006_Annexs1_5.indd 83 4.5.2006 16:12:484.5.2006 16:12:48
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WHO Technical Report Series, No. 937, 2006